Pyrimidine compounds and methods of making and using same

ABSTRACT

Disclosed herein are pyrimidinyl compounds that are contemplated to be modulators of cystic fibrosis transmembrane regulators (CFTR), and methods of making and using same. Also provided are pharmaceutical compositions and methods of treating disorders associated with cystic fibrosis transmembrane regulators, such as airway inflammation, cystic fibrosis, and the like.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 61/354,348, filed Jun. 14, 2010, thecontents of which are hereby incorporated by reference for all purposes.

FIELD OF THE INVENTION

The invention relates to pyrimidine compounds, methods of modulating theactivity of the cystic fibrosis transmembrane regulator, and therapeuticuses of the pyrimidine compounds. In particular, the present inventionrelates to amino-pyrimidinyl and related compounds, methods of usingsuch compounds to modulate the activity of the cystic fibrosistransmembrane regulator in a subject and to treat cystic fibrosis.

BACKGROUND

The cystic fibrosis transmembrane regulator (CFTR) is a protein ofapproximately 1480 amino acids made up of two repeated elements, eachhaving six transmembrane segments and a nucleotide binding domain. Basedon its predicted domain structure, CFTR is a member or a class ofrelated proteins which includes the multi-drug resistance (MDR) orP-glycoprotein, bovine adenyl cyclase, the yeast STE6 protein, as wellas several bacterial amino acid transport proteins. Proteins in thisgroup, characteristically, are involved in pumping molecules into or outof cells. The CFTR has been postulated to regulate the outward flow ofanions from epithelial cells in response to phosphorylation by cyclicAMP-dependent protein kinase or protein kinase C.

Cystic fibrosis (CF) is a lethal, hereditary, autosomal recessivedisease which is caused by mutations in the gene coding for the CFTRCl⁻-channel. By far the most common disease-causing mutation is thedeletion of the codon for phenylalanine 508 (ΔF508) in the primarysequence of wild type CFTR. Over 90% of patients carry at least oneallele of the ΔF508 CFTR mutant gene. The gene product from this mutantgene is a CFTR Cl⁻-channel that is poorly processed within the cell:most of the mutant protein is incorrectly or incompletely folded andbecomes targeted for endoplasmic reticulum-associated degradation(ERAD). The few mutant Cl⁻-channels that pass the quality control orsimply escape the ER before they are degraded will mature through thegolgi and eventually be incorporated into the plasma membrane. These arethought to represent <5% of the level observed in cells expressing wildtype CFTR, resulting in a commensurate low total whole-cellCl⁻-conductance. In addition to the much lower number of channels in theplasma membrane, the open probability of the individual channel proteinsis ˜3-fold reduced compared to wild type CFTR.

For over a decade, efforts have been ongoing to identify small moleculedrugs that can restore the cell CFTR Cl⁻-conductance to levels highenough to ameliorate the effects of CF. These include correctors ofΔF508 CFTR, compounds that can improve the intracellular processing, andpotentiators, compounds which increase the open probability of mutantCFTR channels at the cell surface.

A small molecule, dual-acting potentiator-corrector is expected to be ofgreat benefit for the treatment of most CF patients. To date, it hasproven difficult to develop compounds acting solely by correction of theintracellular processing that can sufficiently increase the number ofchannels in the cell surface to overcome the disease-causing deficiencyin Cl⁻-conductance. On the other hand, potentiation, i.e., increase ofopen probability, of only the mutant channels at the cell surface willnot sufficiently restore Cl⁻-conductance for most CF patients. Adual-acting potentiator-corrector molecule would mechanistically combineaspects of both corrector and potentiator compounds: the number of CFTRchannels at the surface and the channel open probability are increasedin parallel.

SUMMARY

Provided herein are compounds contemplated to be CFTR modulators, andtheir use as, for example, medicinal agents. Also provided arepharmaceutical compositions comprising at least one disclosed compound,or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, and apharmaceutically acceptable carrier.

Accordingly, one aspect of the invention provides a compound of FormulaI:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein thevariables are as defined in the detailed description.

Another aspect of the invention provides a compound of Formula II:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein thevariables are as defined in the detailed description.

Another aspect of the invention provides a compound of Formula III:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein thevariables are as defined in the detailed description.

Another aspect of the invention provides a compound of Formula IV:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein thevariables are as defined in the detailed description.

Also provided herein are methods of treating airway inflammation, suchas in cystic fibrosis, comprising administering to a subject in needthereof a therapeutically effective amount of a compound describedherein, e.g., a compound of Formula I, IA, II, IIA, III, or IV. Alsodescribed herein are compositions that include a compound, e.g., acompound of I, IA, II, IIA, III, or IV, and a pharmaceuticallyacceptable excipient.

The invention further provides methods of modulating the activity of oneor more cystic fibrosis transmembrane regulators comprising, forexample, exposing said receptor to a compound described herein, e.g., acompound of Formula I, IA, II, IIA, III, or IV.

Also provided herein are methods of treating a disease associated withexpression or activity of one or more cystic fibrosis transmembraneregulators in a subject comprising administering to the subject atherapeutically effective amount of a disclosed compound. For example,provided herein are methods of treating chronic obstructive pulmonarydisease, dry eye disease, and Sjögren's syndrome, comprisingadministering a compound described herein, e.g., a compound of FormulaI, IA, II, IIA, III, or IV. Also provided are use of a compounddescribed herein for therapy and/or the manufacture of a medicament forthe treatment of disease associated with cystic fibrosis transmembraneregulators.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Before further description of the presentinvention, certain terms employed in the specification, examples andappended claims are collected here. These definitions should be read inlight of the remainder of the disclosure and understood as by a personof skill in the art. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by a person of ordinary skill in the art.

I. DEFINITIONS

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The term “aldehyde” or “formyl” as used herein refers to the radical—CHO.

The term “alkanoyl” as used herein refers to a radical —O—CO-alkyl.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl,respectively. Exemplary alkenyl groups include, but are not limited to,vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl, etc.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). Exemplary alkoxy groups include, but are not limitedto methoxy, ethoxy, etc.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-12, 2-8, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkynyl, C₂-C₈alkynyl, and C₂-C₆alkynyl,respectively. Exemplary alkynyl groups include, but are not limited to,ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl, etc.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently selectedfrom alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro. Theamide can be attached to another group through the carbon, the nitrogen,R_(b), R_(c), or R_(a). The amide also may be cyclic, for example R_(b)and R_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to6-membered ring. The term “carboxamido” refers to the structure—C(O)NR_(b)R_(c). In certain embodiments, the carboxamido group isrepresented by the radical —C(O)NRR′, where R and R′ may be the same ordifferent and selected from, for example, alkyl, aryl, arylalkyl,cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.

The term “amidino” as used herein refers to a radical of the form—C(═NR)NR′R″ where R, R′, and R″ can each independently be selected fromalkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone and nitro.

The term “amine” or “amino” as used herein refers to a radical of theform —NR_(d)R_(e), —N(R_(d))R_(e)—, or —R_(e)N(R_(d))R_(f)— where R_(d),R_(e), and R_(f) are independently selected from alkoxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, and nitro. The amino can be attached to the parentmolecular group through the nitrogen, R_(d), R_(e) or R_(f). The aminoalso may be cyclic, for example any two of R_(d), R_(e) or R_(f) may bejoined together or with the N to form a 3- to 12-membered ring, e.g.,morpholino or piperidinyl. The term amino also includes thecorresponding quaternary ammonium salt of any amino group, e.g.,—[N(Rd)(Re)(Rf)]+. Exemplary amino groups include aminoalkyl groups,wherein at least one of R_(d), R_(e), or R_(f) is an alkyl group.

The term “aryl” as used herein refers to refers to a mono-, bi-, orother multi-carbocyclic, aromatic ring system. Unless specifiedotherwise, the aromatic ring is optionally substituted at one or morering positions with substituents independently selected from alkanoyl,alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl,azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino,ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,sulfonamido, sulfonyl and thiocarbonyl. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is aromatic, e.g., the othercyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/oraryls. Exemplary aryl groups include, but are not limited to, phenyl,tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as wellas benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.In certain embodiments, the aryl group is not substituted, i.e., it isunsubstituted.

The term “arylalkyl” (also presented as “aralkyl”) as used herein refersto an aryl group having at least one alkyl substituent, e.g.-aryl-alkyl-. Exemplary arylalkyl groups include, but are not limitedto, arylalkyls having a monocyclic aromatic ring system, wherein thering comprises 6 carbon atoms. For example, “phenylalkyl” includesphenylC₁₋₄alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, etc.

The term “azido” as used herein refers to the radical —N₃.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i-), or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide,sulfonyl, and sulfonamide. Exemplary carbamates include, but are notlimited to, arylcarbamates or heteroaryl carbamates, e.g., wherein atleast one of R_(g), R_(h) and R_(i) are independently selected from arylor heteroaryl, such as phenyl and pyridinyl.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a monovalent saturated orunsaturated cyclic, bicyclic, or bridged cyclic (e.g.,adamantyl)hydrocarbon group of 3-10, 3-8, 4-8, or 4-6 carbons, referredto herein, e.g., as “C₄₋₈cycloalkyl,” derived from a cycloalkane.Exemplary cycloalkyl groups include, but are not limited to,cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes, cyclobutanesand cyclopropanes. Unless specified otherwise, cycloalkyl groups areoptionally substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl,amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate,phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl andthiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl,or heterocyclyl groups. In certain embodiments, the cycloalkyl group isnot substituted, i.e., it is unsubstituted.

The term “ether” refers to a radical having the structure—R_(l)O—R_(m)—, where R_(l) and R_(m) can independently be alkyl, aryl,cycloalkyl, heterocyclyl, or ether. The ether can be attached to theparent molecular group through R_(l) or R_(m). Exemplary ethers include,but are not limited to, alkoxyalkyl and alkoxyaryl groups. Ether alsoincludes polyethers, e.g., where one or both of R_(l) and R_(m) areethers.

The terms “halo” or “halogen” or “Hal” as used herein refer to F, Cl,Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms.

The terms “heteroaryl” as used herein refers to a 5-15 membered mono-,bi-, or other multi-cyclic, aromatic ring system containing one or moreheteroatoms, for example one to four heteroatoms, such as nitrogen,oxygen, and sulfur. Heteroaryls can also be fused to non-aromatic rings.Unless specified otherwise, the heteroaryl ring is optionallysubstituted at one or more positions with such substituents as describedabove, as for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato,phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.Illustrative examples of heteroaryl groups include, but are not limitedto, acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furazanyl, furyl,imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl,oxazolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyrazolyl, pyrazyl, pyridazinyl, pyridinyl, pyrimidilyl,pyrimidyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl,quinoxaloyl, quinazolinyl, tetrazolyl, thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thiophenyl, triazinyl, (1,2,3,)- and(1,2,4)-triazolyl, and the like. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2 to 5 carbon atoms and 1 to 3 heteroatoms. In certainembodiments, the heteroaryl group is not substituted, i.e., it isunsubstituted.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated 3- to 10-membered ringstructures, alternatively 3- to 7-membered rings, whose ring structuresinclude one to four heteroatoms, such as nitrogen, oxygen, and sulfur.Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems.A heterocycle may be fused to one or more aryl, partially unsaturated,or saturated rings. Heterocyclyl groups include, for example, biotinyl,chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl,phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl,pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl,thiopyranyl, xanthenyl, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. Unless specifiedotherwise, the heterocyclic ring is optionally substituted at one ormore positions with substituents such as alkanoyl, alkoxy, alkyl,alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, theheterocyclcyl group is not substituted, i.e., it is unsubstituted.

The term “heterocycloalkyl” is art-recognized and refers to a saturatedheterocyclyl group as defined above.

The term “heterocyclylalkoxy” as used herein refers to a heterocyclylattached to an alkoxy group.

The term “heterocyclyloxyalkyl” refers to a heterocyclyl attached to anoxygen (—O—), which is attached to an alkyl group.

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical—OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy radicalattached to an alkyl group.

The term “imino” as used herein refers to the radical —C(═N)—R″, whereR″ can be, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclyl, and ketone.

The term “nitro” as used herein refers to the radical —NO₂.

The term “phenylene” as used herein refers a multi-radical of benzene,e.g.,

or

The term “heteroarylene” is art-recognized and refers to a multi-radicalof a heteroaryl group.

The term “phosphate” as used herein refers to the radical—OP(O)(OR_(aa))₂ or its anions. The term “phosphanato” refers to theradical —P(O)(OR_(aa))₂ or its anions. The term “phosphinato” refers tothe radical —PR_(aa)(O)(OR_(aa)) or its anion, where each R_(aa) can beselected from, for example, alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, hydrogen, haloalkyl, heteroaryl, and heterocyclyl.

The term “sulfate” as used herein refers to the radical —OS(O)(OR_(aa))₂or its anions, where R_(aa) is defined above.

The term “sulfonamide” or “sulfonamido” as used herein refers to aradical having the structure —N(R_(r))—S(O)₂—R_(s)— or—S(O)₂—N(R_(r))R_(s), where R_(r), and R_(s) can be, for example,hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplarysulfonamides include alkylsulfonamides (e.g., where R_(s) is alkyl),arylsulfonamides (e.g., where R_(s) is aryl), cycloalkyl sulfonamides(e.g., where R_(s) is cycloalkyl), and heterocyclyl sulfonamides (e.g.,where R_(s) is heterocyclyl), etc.

The term “sulfonyl” as used herein refers to a radical having thestructure R_(u)SO₂—, where R_(u) can be alkyl, aryl, cycloalkyl, andheterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.

The term “sulfide” as used herein refers to the radical having thestructure R_(z)S—, where R_(z) can be alkoxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester,ether, formyl, haloalkyl, heteroaryl, heterocyclyl, and ketone. The term“alkylsulfide” as used herein refers to an alkyl group attached to asulfur atom. Exemplary sulfides include “thio,” which as used hereinrefers to an —SH radical.

The term “thiocarbonyl” or “thiocarboxy” as used herein refers tocompounds and moieties which contain a carbon connected with a doublebond to a sulfur atom.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds of the invention can beadministered to a mammal, such as a human, but can also be other mammalssuch as an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), farm animals (e.g., cows,sheep, pigs, horses, and the like) and laboratory animals (e.g., rats,mice, guinea pigs, and the like). The mammal treated in the methods ofthe invention is desirably a mammal in whom modulation of cysticfibrosis transmembrane regulators is desired.

“Modulation” includes antagonism (e.g., inhibition), agonism, partialantagonism and/or partial agonism. Modulators may be dual actingcorrector/potentiator compounds. In one embodiment, a modulator is acorrector compound. In another embodiment, a modulator is a potentiatorcompound.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. The compounds of the invention are administered intherapeutically effective amounts to treat a disease. Alternatively, atherapeutically effective amount of a compound is the quantity requiredto achieve a desired therapeutic and/or prophylactic effect, such as anamount which results in the prevention of or a decrease in the symptomsassociated with a disease associated with cystic fibrosis transmembraneregulators.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe present compositions. Compounds included in the present compositionsthat are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that include an aminomoiety may form pharmaceutically acceptable salts with various aminoacids, in addition to the acids mentioned above. Compounds included inthe present compositions that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include alkali metal or alkaline earth metalsalts and, particularly, calcium, magnesium, sodium, lithium, zinc,potassium, and iron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers by wellknown methods, such as chiral-phase gas chromatography, chiral-phasehigh performance liquid chromatography, crystallizing the compound as achiral salt complex, or crystallizing the compound in a chiral solvent.Stereoisomers can also be obtained from stereomerically-pureintermediates, reagents, and catalysts by well known asymmetricsynthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. The present invention encompasses the various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein can exist in solvated as well asunsolvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. In one embodiment, thecompound is amorphous. In one embodiment, the compound is a polymorph.In another embodiment, the compound is in a crystalline form.

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in, e.g., the Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

The term “prodrug” refers to compounds that are transformed in vivo toyield a disclosed compound or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms, such as through hydrolysis in blood. For example, ifa compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound contains a carboxylic acid functionalgroup, a prodrug can comprise an ester formed by the replacement of thehydrogen atom of the acid group with a group such as (C₁-C₈)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbonatoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a compound of the invention contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylacyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

If a compound of the invention incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl whereR and R′ are each independently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl,benzyl, or R-carbonyl is a natural α-aminoacyl or naturalα-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H,(C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is(C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino, morpholino, piperidin-1-yl orpyrrolidin-1-yl.

II. PYRIMIDINYL COMPOUNDS & PHARMACEUTICAL COMPOSITIONS

One aspect of the invention provides a compound of Formula I:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is —O—(CR₆R₇)_(n)-A₂, —N(R₆)(CR₆R₇)_(n)-A₂, —S—(CR₆R₇)_(n)-A₂, orheterocycloalkyl, wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₂ is —O-heterocycloalkyl, —O-heterocycloalkenyl, —Y-heterocycloalkyl,—Y-heterocycloalkenyl, heterocycloalkyl, -heterocycloalkenyl,-cycloalkyl, -cycloalkenyl, —(CR₆R₇)_(n)—C₁-C₆alkoxyl,—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, C₁-C₆alkoxyl, halogen, —CF₃, —CH₂F, —CHF₂,—OCF₃, —OCH₂F, hydroxyl, or C₁-C₆alkyl, wherein said heterocycloalkyl,heterocycloalkenyl, cycloalkyl, and cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—OCF₃, —N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉,—N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₃ is hydrogen, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —OCF₃, —OCH₂F,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, or —SO₂R₁₀;

R₄ is hydrogen, halogen, C₁-C₄alkyl, cyclopropyl, —CN, or —CF₃

R₅ is hydrogen or C₁-C₄alkyl;

R₆ and R₇ each represent independently for each occurrence hydrogen oralkyl, or when R₆ and R₇ are attached to the same atom, R₆ and R₇ areoptionally taken together with the atom to which they are attached toform a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₈ and R₉ each represent independently for each occurrence hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; or when R₈ and R₉ are attached to the same atom, R₈ andR₉ are optionally taken together with the atom to which they areattached to form a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

A₁ is phenylene or a monocyclic heteroarylene group;

A₂ is a heterocycloalkyl group containing at least one nitrogen orsulfur atom, and wherein said heterocycloalkyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₆alkoxyl, C₃-C₆cycloalkyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —N(R₈)R₉,—CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

W is C₁-C₆alkyl or C₄-C₁₀cycloalkyl, each of which are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl,—OC₁-C₆alkyl, —O-cycloalkyl, —OH, —CF₃, and fluoro;

Y is —N(R₈)—, —S—, —S(O)—, or —S(O)₂—;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, R₁ is —O—(CR₆R₇)_(n)-A₂ or a heterocycloalkylgroup optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, R₁ is —O—(CR₆R₇)_(n)-A₂.

In certain embodiments, A₂ is a heterocycloalkyl group containing atleast one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, A₂ is a heterocycloalkyl group containing at least onenitrogen or sulfur atom, and wherein said heterocycloalkyl group issubstituted with one or more substituents independently selected fromthe group consisting of —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, A₂ is a 3-6 membered heterocycloalkyl group containing atleast one nitrogen, and wherein said heterocycloalkyl group issubstituted with —SO₂R₁₀. In certain embodiments, A₂ is an azetidinyl,pyrrolidinyl, piperidinyl or morpholinyl, each of which is substitutedwith —CON(R₈)R₉, —SO₂N(R₈)R₉, or —SO₂R₁₀. In certain embodiments, A₂ isazetidinyl substituted with —CON(R₈)R₉, —SO₂N(R₈)R₉, or —SO₂R₁₀.

In certain other embodiments, A₂ is a heterocycloalkyl group containingat least one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is substituted with one or more substituents independentlyselected from the group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁₀. In certain embodiments, A₂ is a 3-6 memberedheterocycloalkyl group containing at least one nitrogen, and whereinsaid heterocycloalkyl group is substituted with —CO₂R₈, —SO₂N(R₈)R₉,—SO₂R₁₀. In certain embodiments, A₂ is an azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl, each of which is substituted with—CON(R₈)R₉, —CO₂R₈, —SO₂N(R₈)R₉, or —SO₂R₁₀. In certain embodiments, A₂is azetidinyl, pyrrolidinyl, or piperidinyl, each substituted with—CON(R₈)R₉, —CO₂R₈, —SO₂N(R₈)R₉, or —SO₂R₁₀.

In certain embodiments, A₂ is one of the following:

In certain other embodiments, A₂ is

In certain embodiments, n is 0 or 1. In certain other embodiments, n is0. In certain other embodiments, n is 1. In certain embodiments, m is 1.

In certain embodiments, R₁ is a heterocycloalkyl group containing atleast one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl,—C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certain embodiments, R₁is a heterocycloalkyl group optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain embodiments, R₁ is a heterocycloalkyl group containing at leastone nitrogen or sulfur atom, and wherein said heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen and C₁-C₆alkyl. In certainembodiments, R₁ is morpholino, azetidinyl, piperidinyl, or pyrrolidinyl.

In certain embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl,—N(R₈)R₉, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, R₂ is —O-heterocycloalkyl or —O—(CR₆R₇)_(n)—C₁-C₆alkoxyl;wherein said heterocycloalkyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, —CO₂R₈, and —CON(R₈)R₉. In certain embodiments, R₂is —O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen and C₁-C₆alkyl. In certain embodiments,R₂ is morpholinyl, —O-tetrahydrofuranyl, O-tetrahydropyranyl,—O-pyrrolidinyl, or —O-piperidinyl. In certain embodiments, R₂ is—O-tetrahydrofuranyl.

In certain other embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉,—SO₂N(R₈)R₉, and —SO₂R₁₀. In certain other embodiments, R₂ is—O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain other embodiments, R₂ is morpholinyl, —O-tetrahydrofuranyl,O-tetrahydropyranyl, —O-pyrrolidinyl, O-azetidinyl or —O-piperidinyl;wherein said pyrrolidinyl, azetidinyl or piperidinyl each independentlyis optionally substituted with one or more substituents independentlyselected from the group consisting of, —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁

In certain embodiments, R₃ is hydrogen, halogen, —OCF₃, —OCH₂F, —CF₃,C₁-C₆alkyl, or C₁-C₆alkoxy. In certain embodiments, R₃ is hydrogen,halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl, —NR₈R₉, —CN, or —C(O)R₁₀.In certain embodiments, R₃ is hydrogen, halogen, C₁-C₆alkyl, orC₁-C₆alkoxyl. In certain embodiments, R₃ is hydrogen, and m is 1.

In certain embodiments, R₄ is hydrogen or methyl, and R₅ is hydrogen. Incertain embodiments, R₄ and R₅ are hydrogen. In certain embodiments, R₄is methyl, and R₅ is hydrogen. In certain embodiments, R₆ and R₇ eachrepresent independently for each occurrence hydrogen or methyl.

In certain embodiments, R₈ and R₉ each represent independently for eachoccurrence hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl,cyclopropyl, cyclobutyl, phenyl, or benzyl, or R₈ and R₉ are optionallytaken together with the atom to which they are attached to form a 3-6membered cycloalkyl or heterocycloalkyl group. In certain embodiments,R₈ and R₉ each represent independently for each occurrence hydrogen,methyl, ethyl or cyclopropyl. In certain embodiments, R₈ and R₉ eachrepresent independently for each occurrence hydrogen, methyl, ethyl,propyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl. In certainembodiments, R₈ and R₉ each represent independently for each occurrencehydrogen or methyl. In certain embodiments, R₁₀ is methyl, ethyl,n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl.

In certain embodiments, A₁ is phenylene. In certain embodiments, A₁ is apyridinyl diradical.

In certain embodiments, W is C₅-C₁₀cycloalkyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of C₁-C₆alkyl and fluoro. In certain embodiments, W isC₅-C₁₀cycloalkyl optionally substituted with one or two substituentsindependently selected from the group consisting of C₁-C₆alkyl, —CF₃,and fluoro. In certain embodiments, W is cyclohexyl substituted with oneor two substituents independently selected from the group consisting ofC₁-C₆alkyl, —CF₃, and fluoro. In certain embodiments, W is selected fromthe group consisting of cyclobutyl, cycloheptyl, cyclohexyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,1-methylcyclohexyl, 1,5-dimethylcyclohexyl, cyclopentyl, isopropyl, andbicyclo[2,2,1]heptyl. In certain embodiments, W is selected from thegroup consisting of cyclobutyl, cyclohexyl, cycloheptyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,cyclopentyl, and —CH₂cyclohexyl. In certain embodiments, W is cyclohexylsubstituted with one or two C₁-C₆alkyl. In certain embodiments, W iscyclohexyl substituted with one or two substituents independentlyselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

In certain embodiments, the compound is selected from the groupconsisting of:N,N-dimethyl-3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-(S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;methyl4-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate;N-((1s,4s)-4-methylcyclohexyl)-4-(1-(methylsulfonyl)piperidin-4-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;and4-(1-(cyclopropylsulfonyl)azetidin-3-yloxy)-N-((1s,4s)-4-methylcyclohexyl)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;or a pharmaceutically acceptable salt or N-oxide thereof.

Another aspect of the invention provides a compound of Formula IA:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is —O—(CR₆R₇)_(n)-A₂, or a heterocycloalkyl group containing at leastone nitrogen or sulfur atom, and wherein said heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl,—CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, and —SO₂R₁₀;

R₂ is —O-heterocycloalkyl, heterocycloalkyl, or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, —C(O)R₁₀,—CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, and —N(R₈)SO₂R₁₀;

R₃ is hydrogen, halogen, or methyl;

R₄, R₅, R₆, R₇, R₈, and R₉ each represent independently for eachoccurrence hydrogen or methyl;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl, orheterocycloalkyl;

A₂ is a heterocycloalkyl group containing at least one nitrogen orsulfur atom, and wherein said heterocycloalkyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₁-C₆alkyl, C₁-C₆alkoxyl, —C(O)R₁₀, —CO₂R₈,—OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, and—SO₂R₁₀;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, the definition of the variables for Formula IAcorrespond to one or more of the embodiments described above for thedefinitions of the variables associated with Formula I to the extent thedefinition does not expand the scope of compounds embraced by Formula IAbeyond that defined originally.

Another aspect of the invention provides a compound of Formula II:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is a —O—(CR₆R₇)_(n)-heterocycloalkyl group, wherein theheterocycloalkyl group is a 5-7 membered ring containing 1 or 2 ringoxygen or sulfur atoms and the ring is optionally substituted with oneor more substituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₂ is —O—(CR₆R₇)_(n)-heterocycloalkyl, heterocycloalkyl, a 5-6 memberedheteroaryl, —O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, —(CR₆R₇)_(n)-heterocycloalkyl,—C(O)-heterocycloalkyl, —CON(R₈)R₉, —(CR₆R₇)_(n)—N(R₈)R₉,—(CR₆R₇)_(n)—N(R₈)COR₁₀, —CO₂R₈, —N(R₈)CO₂R₁₀, —C(O)N(R₈)S(O)₂N(R₈)R₉,—C(O)N—CN, or —SO₂N(R₈)C(O)R₁₀; wherein the heterocycloalkyl groups areoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈,—OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉,—N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀; provided that R₂ is not morpholinyl;

R₃ is hydrogen, halogen, —CF₃, —CH₂F, —CHF₂, —OCH₂F, C₁-C₆alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, methoxy, ethoxy, hydroxyl, —N(R₈)R₉, —CN,—C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, or—SO₂R₁₀;

R₄ and R₅ each represent independently for each occurrence hydrogen orC₁-C₄alkyl;

R₆ and R₇ each represent independently for each occurrence hydrogen oralkyl, or when R₆ and R₇ are attached to the same atom, R₆ and R₇ areoptionally taken together with the atom to which they are attached toform a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₈ and R₉ each represent independently for each occurrence hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; or when R₈ and R₉ are attached to the same atom, R₈ andR₉ are optionally taken together with the atom to which they areattached to form a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

W is C₁-C₆alkyl or C₄-C₁₀cycloalkyl, each of which are optionallysubstituted with one or two substituents independently selected from thegroup consisting of C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl,—OC₁-C₆alkyl, —O-cycloalkyl, —OH, and fluoro;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, R₁ is a —O—(CR₆R₇)_(n)-heterocycloalkyl group,wherein the heterocycloalkyl group is a 5-7 membered ring containing 1or 2 ring oxygen or sulfur atoms and the ring is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl, —N(R₈)R₉,—C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉,—N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certain embodiments, R₁ is a—O—(CR₆R₇)_(n)—C₅-C₇heterocycloalkyl group containing 1 or 2 ring oxygenor sulfur atoms, and wherein the heterocycloalkyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, —C(O)R₁₀,—CO₂R₈, —CONR₈R₉, —NR₈COR₁₀, —NR₈SO₂R₁₀, —SO₂NR₈R₉, and —SO₂R₁₀. Incertain embodiments, R₁ is a —O—(CR₆R₇)_(n)-heterocycloalkyl group,wherein the heterocycloalkyl group is a 5-7 membered ring containing 1or 2 ring oxygen or sulfur atoms and the ring is optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen and C₁-C₆alkyl. In certain embodiments, R₁ is—O—(CR₆R₇)_(n)-tetrahydrofuranyl, —O—(CR₆R₇)_(n)-tetrahydropyranyl,—O—(CR₆R₇)_(n)-dioxanyl, or —O—(CR₆R₇)_(n)-oxetanyl. In certainembodiments, R₁ is —O—(CR₆R₇)_(n)-tetrahydrofuranyl or—O—(CR₆R₇)_(n)-tetrahydropyranyl.

In certain embodiments, R₂ is —O—(CR₆R₇)_(n)-heterocycloalkyl,—O-heterocycloalkyl, or heterocycloalkyl; wherein the heterocycloalkylgroups are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl,C₁-C₆alkoxyl, hydroxyl, —N(R₈)R₉, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉,—CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain embodiments, R₂ is —O—(CR₆R₇)_(n)— heterocycloalkyl or—O-heterocycloalkyl; wherein the heterocycloalkyl groups are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, and C₁-C₆alkoxyl. Incertain embodiments, R₂ is —O—(CR₆R₇)_(n)-tetrahydrofuranyl,—O—(CR₆R₇)_(n)-tetrahydropyranyl, —O—(CR₆R₇)_(n)-morpholinyl,—O-tetrahydrofuranyl, or —O-tetrahydropyranyl. In certain embodiments,R₂ is —O—(CR₆R₇)_(n)-tetrahydrofuranyl,—O—(CR₆R₇)_(n)-tetrahydropyranyl, —O—(CR₆R₇)_(n)-morpholinyl,—O-tetrahydrofuranyl, —O—(CR₆R₇)_(n)-oxetanyl, or —O-tetrahydropyranyl.

In certain embodiments, R₃ is hydrogen, halogen, C₁-C₆alkyl,C₁-C₆alkoxyl, hydroxyl, —NR₈R₉, —CN, or —C(O)R₁₀. In certainembodiments, R₃ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆alkoxyl. Incertain embodiments, R₃ is hydrogen, and m is 1.

In certain embodiments, R₄ is hydrogen or methyl, and R₅ is hydrogen. Incertain embodiments, R₄ and R₅ are hydrogen. In certain embodiments, R₄is methyl, and R₅ is hydrogen. In certain embodiments, R₆ and R₇ eachrepresent independently for each occurrence hydrogen or methyl.

In certain embodiments, R₈ and R₉ each represent independently for eachoccurrence hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl,cyclopropyl, cyclobutyl, phenyl, or benzyl. In certain embodiments, R₈and R₉ each represent independently for each occurrence hydrogen,methyl, isopropyl, or cyclopropyl. In certain embodiments, R₈ and R₉each represent independently for each occurrence hydrogen or methyl. Incertain embodiments, R₁₀ is methyl, ethyl, n-propyl, isopropyl, butyl,cyclopropyl, cyclobutyl, phenyl, or benzyl.

In certain embodiments, n is 0. In certain embodiments, n is 1.

In certain embodiments, W is C₄-C₁₀cycloalkyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of C₁-C₆alkyl, —CF₃, and fluoro. In certain embodiments, W isselected from the group consisting of cyclobutyl, cycloheptyl,cyclohexyl, 4-methylcyclohexyl, 4-ethylcyclohexyl,4-trifluoromethylcyclohexyl, 1-methylcyclohexyl, 1,5-dimethylcyclohexyl,cyclopentyl, isopropyl, and bicyclo[2,2,1]heptyl. In certainembodiments, W is selected from the group consisting of cyclobutyl,cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4-ethylcyclohexyl,4-trifluoromethylcyclohexyl, cyclopentyl, and —CH₂cyclohexyl. In certainembodiments, W is cyclohexyl substituted with one or two substituentsindependently selected from the group consisting of C₁-C₆alkyl, —CF₃,and fluoro. In certain embodiments, W is cyclohexyl substituted with oneor two C₁-C₆alkyl. In certain embodiments, W is cyclohexyl substitutedwith one or two substituents independently selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, and tert-butyl.

Another aspect of the invention provides a compound of Formula IIA:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is a —O—(CR₆R₇)_(n)-heterocycloalkyl group, wherein theheterocycloalkyl group is an unsubstituted 5-7 membered ring containing1 or 2 ring oxygen or sulfur atoms;

R₂ is —O—(CR₆R₇)_(n)-heterocycloalkyl, —O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, or—(CR₆R₇)_(n)-heterocycloalkyl; wherein the heterocycloalkyl groups areoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl,hydroxyl, —N(R₈)R₉, —C(O)R₁₀, —CO₂R₈, and —CON(R₈)R₉; provided that R₂is not morpholinyl;

R₃ is hydrogen, halogen, or C₁-C₆alkyl;

R₄, R₅, R₆, R₇, R₈, and R₉ each represent independently for eachoccurrence hydrogen or methyl;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl, orheterocycloalkyl;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, the definition of the variables for Formula IIAcorrespond to one or more of the embodiments described above for thedefinitions of the variables associated with Formula II to the extentthe definition does not expand the scope of compounds embraced byFormula IIA beyond that defined originally.

Another aspect of the invention provides a compound of Formula III:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is —O—(CR₆R₇)_(n)-A₂, —N(R₆)(CR₆R₇)_(n)-A₂, —S—(CR₆R₇)_(n)-A₂, orheterocycloalkyl, wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₂ is —O-heterocycloalkyl, —O-heterocycloalkenyl, —Y-heterocycloalkyl,—Y-heterocycloalkenyl, heterocycloalkyl, -heterocycloalkenyl,-cycloalkyl, -cycloalkenyl, —(CR₆R₇)_(n)—C₁-C₆alkoxyl,—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, C₁-C₆alkoxyl, halogen, —CF₃, —CH₂F, —CHF₂,—OCF₃, —OCH₂F, hydroxyl, or C₁-C₆alkyl, wherein said heterocycloalkyl,heterocycloalkenyl, cycloalkyl, and cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—OCF₃, —N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉,—N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₃ is hydrogen, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —OCF₃, —OCH₂F,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, or —SO₂R₁₀;

R₄ is C₁-C₄alkyl, —(CR₆R₇)_(n)—C₁-C₆alkoxyl, or —CO₂C₁-C₆alkyl;

R₅ is hydrogen or C₁-C₄alkyl;

R₆ and R₇ each represent independently for each occurrence hydrogen oralkyl, or when R₆ and R₇ are attached to the same atom, R₆ and R₇ areoptionally taken together with the atom to which they are attached toform a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₈ and R₉ each represent independently for each occurrence hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; or when R₈ and R₉ are attached to the same atom, R₈ andR₉ are optionally taken together with the atom to which they areattached to form a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

A₁ is phenylene or a monocyclic heteroarylene group;

A₂ is heterocycloalkyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl,C₃-C₆cycloalkyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —N(R₈)R₉, —CN, —C(O)R₁₀,—CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉,—N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

W is C₁-C₆alkyl or C₄-C₁₀cycloalkyl, each of which are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl,—OC₁-C₆alkyl, —O-cycloalkyl, —OH, —CF₃, and fluoro;

Y is —N(R₈)—, —S—, —S(O)—, or —S(O)₂—;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, R₁ is —O—(CR₆R₇)_(n)-A₂ or a heterocycloalkylgroup optionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, R₁ is —O—(CR₆R₇)_(n)-A₂.

In certain embodiments, A₂ is a heterocycloalkyl group containing atleast one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, A₂ is a heterocycloalkyl group containing at least onenitrogen or sulfur atom, and wherein said heterocycloalkyl group issubstituted with one or more substituents independently selected fromthe group consisting of —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, A₂ is a 3-6 membered heterocycloalkyl group containing atleast one nitrogen, and wherein said heterocycloalkyl group issubstituted with —SO₂R₁₀. In certain embodiments, A₂ is an azetidinyl,pyrrolidinyl, piperidinyl or morpholinyl, each of which is substitutedwith —CON(R₈)R₉, —SO₂N(R₈)R₉, or —SO₂R₁₀. In certain embodiments, A₂ isazetidinyl substituted with —CON(R₈)R₉, —SO₂N(R₈)R₉, or —SO₂R₁₀.

In certain other embodiments, A₂ is a heterocycloalkyl group containingat least one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is substituted with one or more substituents independentlyselected from the group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁₀. In certain embodiments, A₂ is a 3-6 memberedheterocycloalkyl group containing at least one nitrogen, and whereinsaid heterocycloalkyl group is substituted with —CO₂R₈, —SO₂N(R₈)R₉, or—SO₂R₁₀. In certain embodiments, A₂ is an azetidinyl, pyrrolidinyl,piperidinyl or morpholinyl, each of which is substituted with—CON(R₈)R₉, —CO₂R₈, —SO₂N(R₈)R₉, or —SO₂R₁₀. In certain embodiments, A₂is azetidinyl, pyrrolidinyl, or piperidinyl, each substituted with—CON(R₈)R₉, —CO₂R₈, —SO₂N(R₈)R₉, or —SO₂R₁₀.

In certain embodiments, A₂ is one of the following:

In certain other embodiments, A₂ is

In certain embodiments, n is 0 or 1. In certain other embodiments, n is0. In certain other embodiments, n is 1. In certain embodiments, m is 1.

In certain embodiments, R₁ is a heterocycloalkyl group containing atleast one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, C₁-C₆alkyl,—C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certain embodiments, R₁is a heterocycloalkyl group optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain embodiments, R₁ is a heterocycloalkyl group containing at leastone nitrogen or sulfur atom, and wherein said heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen and C₁-C₆alkyl. In certainembodiments, R₁ is morpholino, azetidinyl, piperidinyl, or pyrrolidinyl.

In certain embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl,—N(R₈)R₉, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, R₂ is —O-heterocycloalkyl or —O—(CR₆R₇)_(n)—C₁-C₆alkoxyl;wherein said heterocycloalkyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, —CO₂R₈, and —CON(R₈)R₉. In certain embodiments, R₂is —O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen and C₁-C₆alkyl. In certain embodiments,R₂ is morpholinyl, —O-tetrahydrofuranyl, O-tetrahydropyranyl,—O-pyrrolidinyl, or —O-piperidinyl. In certain embodiments, R₂ is—O-tetrahydrofuranyl.

In certain other embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉,—SO₂N(R₈)R₉, and —SO₂R₁₀. In certain other embodiments, R₂ is—O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain other embodiments, R₂ is morpholinyl, —O-tetrahydrofuranyl,O-tetrahydropyranyl, —O-pyrrolidinyl, O-azetidinyl or —O-piperidinyl;wherein said pyrrolidinyl, azetidinyl or piperidinyl each independentlyis optionally substituted with one or more substituents independentlyselected from the group consisting of, —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁

In certain embodiments, R₃ is hydrogen, halogen, —OCF₃, —OCH₂F, —CF₃,C₁-C₆alkyl, or C₁-C₆alkoxy. In certain embodiments, R₃ is halogen,C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl, —NR₈R₉, —CN, or —C(O)R₁₀. In certainembodiments, R₃ is halogen, C₁-C₆alkyl, or C₁-C₆alkoxyl. In certainembodiments, R₃ is hydrogen, and m is 1.

In certain embodiments, R₅ is hydrogen. In certain embodiments, R₆ andR₇ each represent independently for each occurrence hydrogen or methyl.

In certain embodiments, R₈ and R₉ each represent independently for eachoccurrence hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl,cyclopropyl, cyclobutyl, phenyl, or benzyl, or R₈ and R₉ are optionallytaken together with the atom to which they are attached to form a 3-6membered cycloalkyl or heterocycloalkyl group. In certain embodiments,R₈ and R₉ each represent independently for each occurrence hydrogen,methyl, ethyl or cyclopropyl. In certain embodiments, R₈ and R₉ eachrepresent independently for each occurrence hydrogen, methyl, ethyl,propyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl. In certainembodiments, R₈ and R₉ each represent independently for each occurrencehydrogen or methyl. In certain embodiments, R₁₀ is methyl, ethyl,n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl.

In certain embodiments, A₁ is phenylene.

In certain embodiments, W is C₅-C₁₀cycloalkyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of C₁-C₆alkyl and fluoro. In certain embodiments, W isC₅-C₁₀cycloalkyl optionally substituted with one or two substituentsindependently selected from the group consisting of C₁-C₆alkyl, —CF₃,and fluoro. In certain embodiments, W is cyclohexyl substituted with oneor two substituents independently selected from the group consisting ofC₁-C₆alkyl, —CF₃, and fluoro. In certain embodiments, W is selected fromthe group consisting of cyclobutyl, cycloheptyl, cyclohexyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,1-methylcyclohexyl, 1,5-dimethylcyclohexyl, cyclopentyl, isopropyl, andbicyclo[2,2,1]heptyl. In certain embodiments, W is selected from thegroup consisting of cyclobutyl, cyclohexyl, cycloheptyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,cyclopentyl, and —CH₂cyclohexyl. In certain embodiments, W is cyclohexylsubstituted with one or two C₁-C₆alkyl. In certain embodiments, W iscyclohexyl substituted with one or two substituents independentlyselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

Another aspect of the invention provides a compound of Formula IV:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein:

R₁ is —(CR₆R₇)_(n)—CON(R₈)R₉, —(CR₆R₇)_(n)—N(R₈)COR₁₀,—(CR₆R₇)_(n)—CON(R₈)SO₂R₁₀, —(CR₆R₇)_(n)—C(CH₂OH)(H)—(CR₆R₇)_(n)—OH, or—(CR₆R₇)_(n)—C₁-C₆alkoxyl;

R₂ is —O-heterocycloalkyl, —O-heterocycloalkenyl, —Y-heterocycloalkyl,—Y-heterocycloalkenyl, heterocycloalkyl, -heterocycloalkenyl,-cycloalkyl, -cycloalkenyl, —(CR₆R₇)_(n)—C₁-C₆alkoxyl,—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, C₁-C₆alkoxyl, halogen, —CF₃, —CHF, —CHF,—OCF₃, —OCH₂F, hydroxyl, or C₁-C₆alkyl, wherein said heterocycloalkyl,heterocycloalkenyl, cycloalkyl, and cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CHF, —CHF,—OCF₃, —N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉,—N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;

R₃ is hydrogen, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CHF, —CHF, —OCF₃, —OCH₂F,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, or —SO₂R₁₀;

R₄ is hydrogen, halogen, C₁-C₄alkyl, cyclopropyl, —CN, or —CF₃;

R₅ is hydrogen or C₁-C₄alkyl;

R₆ and R₇ each represent independently for each occurrence hydrogen oralkyl, or when R₆ and R₇ are attached to the same atom, R₆ and R₇ areoptionally taken together with the atom to which they are attached toform a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₈ and R₉ each represent independently for each occurrence hydrogen,alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, orheteroaralkyl; or when R₈ and R₉ are attached to the same atom, R₈ andR₉ are optionally taken together with the atom to which they areattached to form a 3-6 membered cycloalkyl or heterocycloalkyl group;

R₁₀ represents independently for each occurrence alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;

A₁ is phenylene or a monocyclic heteroarylene group;

W is C₁-C₆alkyl or C₄-C₁₀cycloalkyl, each of which are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl,—OC₁-C₆alkyl, —O-cycloalkyl, —OH, —CF₃, and fluoro;

Y is —N(R₈)—, —S—, —S(O)—, or —S(O)₂—;

m is 1 or 2; and

n is 0, 1, 2, 3, or 4.

In certain embodiments, n is 0 or 1. In certain other embodiments, n is0. In certain other embodiments, n is 1. In certain embodiments, m is 1.

In certain embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl,—N(R₈)R₉, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀. In certainembodiments, R₂ is —O-heterocycloalkyl or —O—(CR₆R₇)_(n)—C₁-C₆alkoxyl;wherein said heterocycloalkyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆alkyl, —CO₂R₈, and —CON(R₈)R₉. In certain embodiments, R₂is —O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen and C₁-C₆alkyl. In certain embodiments,R₂ is morpholinyl, —O-tetrahydrofuranyl, O-tetrahydropyranyl,—O-pyrrolidinyl, or —O-piperidinyl. In certain embodiments, R₂ is—O-tetrahydrofuranyl.

In certain other embodiments, R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉,—SO₂N(R₈)R₉, and —SO₂R₁₀. In certain other embodiments, R₂ is—O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀. Incertain other embodiments, R₂ is morpholinyl, —O-tetrahydrofuranyl,O-tetrahydropyranyl, —O-pyrrolidinyl, O-azetidinyl or —O-piperidinyl;wherein said pyrrolidinyl, azetidinyl or piperidinyl each independentlyis optionally substituted with one or more substituents independentlyselected from the group consisting of, —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁.

In certain embodiments, R₃ is hydrogen, halogen, —OCF₃, —OCH₂F, —CF₃,C₁-C₆alkyl, or C₁-C₆alkoxy. In certain embodiments, R₃ is halogen,C₁-C₆alkyl, C₁-C₆alkoxyl, hydroxyl, —NR₈R₉, —CN, or —C(O)R₁₀. In certainembodiments, R₃ is halogen, C₁-C₆alkyl, or C₁-C₆alkoxyl. In certainembodiments, R₃ is hydrogen, and m is 1.

In certain embodiments, R₄ is hydrogen or methyl, and R₅ are hydrogen.In certain embodiments, R₄ and R₅ are hydrogen. In certain embodiments,R₄ is methyl; and R₅ is hydrogen. In certain embodiments, R₆ and R₇ eachrepresent independently for each occurrence hydrogen or methyl.

In certain embodiments, R₈ and R₉ each represent independently for eachoccurrence hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl,cyclopropyl, cyclobutyl, phenyl, or benzyl, or R₈ and R₉ are optionallytaken together with the atom to which they are attached to form a 3-6membered cycloalkyl or heterocycloalkyl group. In certain embodiments,R₈ and R₉ each represent independently for each occurrence hydrogen,methyl, ethyl or cyclopropyl. In certain embodiments, R₈ and R₉ eachrepresent independently for each occurrence hydrogen, methyl, ethyl,propyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl. In certainembodiments, R₈ and

R₉ each represent independently for each occurrence hydrogen or methyl.In certain embodiments, R₁₀ is methyl, ethyl, n-propyl, isopropyl,butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl.

In certain embodiments, A₁ is phenylene.

In certain embodiments, W is C₅-C₁₀cycloalkyl optionally substitutedwith one or two substituents independently selected from the groupconsisting of C₁-C₆alkyl and fluoro. In certain embodiments, W isC₅-C₁₀cycloalkyl optionally substituted with one or two substituentsindependently selected from the group consisting of C₁-C₆alkyl, —CF₃,and fluoro. In certain embodiments, W is cyclohexyl substituted with oneor two substituents independently selected from the group consisting ofC₁-C₆alkyl, —CF₃, and fluoro. In certain embodiments, W is selected fromthe group consisting of cyclobutyl, cycloheptyl, cyclohexyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,1-methylcyclohexyl, 1,5-dimethylcyclohexyl, cyclopentyl, isopropyl, andbicyclo[2,2,1]heptyl. In certain embodiments, W is selected from thegroup consisting of cyclobutyl, cyclohexyl, cycloheptyl,4-methylcyclohexyl, 4-ethylcyclohexyl, 4-trifluoromethylcyclohexyl,cyclopentyl, and —CH₂cyclohexyl. In certain embodiments, W is cyclohexylsubstituted with one or two C₁-C₆alkyl. In certain embodiments, W iscyclohexyl substituted with one or two substituents independentlyselected from the group consisting of methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

In certain other embodiments, the compound is one of the compoundslisted in Tables 1 or 2 below or a pharmaceutically acceptable salt orN-oxide thereof

TABLE 1

No. X Y Z I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

In certain other embodiments, the compound isN,N-dimethyl-3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;5-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine;5-(3-methylbenzo[d]isoxazol-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine;N,N-dimethyl-3-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxamide;N-((1s,4S)-4-methylcyclohexyl)-5-(4-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine;4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine;4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine;(R)-methyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate;4-(((R)-1-methylsulfonyl-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine;methyl3-((2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate;4-((1-methylsulfonyl-azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine;methyl4-((2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate;4-((1-methylsulfonyl-piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine;4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethyl)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride; of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethoxy)phenyl)-N-((1S,4S)-4-methylcyclohexyl)pyrimidin-2-amine;4-((R)-tetrahydrofuran-3-yloxy)-N-((1S,4S)-4-methylcyclohexyl)-5-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)pyrimidin-2-amine;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)-azetidin-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholinophenyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine;4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylicacid; or a pharmaceutically acceptable salt or N-oxide thereof.

In certain other embodiments, the compound is the following:

Another aspect of the invention provides a pharmaceutical compositioncomprising a compound disclosed herein formulated together with one ormore pharmaceutically acceptable carriers. These formulations includethose suitable for oral, rectal, topical, buccal and parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous)administration, although the most suitable form of administration in anygiven case will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Multiple methods for preparing compounds described herein are providedin the examples. Further synthetic methods for preparing variouscompounds described herein are provided by the following schemes. Theschemes are given for the purpose of illustrating the invention, but notfor limiting the scope or spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route in Scheme 1 illustrates a general method forpreparing pyrimidine derivatives. The method involves attaching thedesired substituents to the pyrimidine core. The desired —OR′ groupattached at the 4-position of the pyrimidine core can be installed byreacting bromo-dichloropyrimidine A with the appropriate alkali metalalkoxide to provide bromo-chloropyrimidine B. The amino group at the2-position of the pyrimidine ring can be installed by reactingbromo-chloropyrimidine B with the appropriate amino compound (R″—NH₂).The identity of the R″ group is selected based on the desired R″ groupin the final pyrimidine product D. The aryl or heteroaryl group at theC5-position can be installed by reacting an aryl or heteroaryl boronicacid with bromo-pyrimidine C under Suzuki coupling conditions to providefinal product D.

Scheme 2 provides a more detailed exemplary synthetic procedure formaking pyrimidine derivatives having various functional groups (e.g.,alkylamino or alkylalkoxy) at the C6-position of the pyrimidine ring.Chloro-pyrimidinedione A can be obtained from commercial sources andconverted to chloro-bromo-pyrimidinedione B using N-bromo-succinimide(NBS) following procedures described in, for example, Bioorg. & Med.Chem., 2004, 12(13): 3431-3441. Alternatively, compound B can beobtained from commercial sources. The primary chloro group in compound Bcan be displaced by a variety of nucleophilic groups in order to installdifferent functional groups at this position. For example, reaction ofdimethylamine or sodium methoxide with chloro-pyrimidinedione B providesintermediate C. See, for example, Bioorg. & Med. Chem., 2004, 12(13):3431-3441 for further information on this type of synthetic operation.Reaction of intermediate C with phosphorous oxychloride (POCl₃) providesdichloro-bromo-pyrimidine D. The substituent at the C4-position of thepyrimidine ring can be installed by reacting synthetic intermediate Dwith a desired alkoxide. The amino group at the C2-position of thepyrimidine ring and the aryl or heteroaryl group at the C5-position ofthe pyrimidine ring can be installed using procedures describe in Scheme1 to afford final product E.

Scheme 3 provides a more detailed exemplary synthetic procedure formaking pyrimidine derivatives having various functional groups (e.g.,carboxylic acid or carboxamide) at the C6-position of the pyrimidinering. Dioxo-pyrimidine-carbonitrile A can be obtained from commercialsources and converted to bromo-dioxo-pyrimidine-carbonitrile B usingN-bromo-succinimide (NBS). Reaction ofbromo-dioxo-pyrimidine-carbonitrile B with phosphorous oxychloride(POCl₃) provides dichloro-bromo-pyrimidine C. The substituent at the C-4position of the pyrimidine ring can be installed by reacting syntheticintermediate C with a desired alkoxide. The amino group at theC2-position of the pyrimidine ring and the aryl or heteroaryl group atthe C5-position of the pyrimidine ring can be installed using proceduresdescribe in Scheme 1 to afford cyano-pyrimidine E. The cyano group incyano-pyrimidine E can be converted to a carboxylic acid group usingstandard functional group manipulation techniques to provide carboxylicacid F. Finally, the carboxylic group can be converted to variouscarboximide groups using standard functional group manipulationtechniques to provide final compound G. For a description of standardorganic chemistry functional group transformation techniques, see, forexample, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming,eds., 1991-1992).

Scheme 4 provides an alternative approach to making pyrimidinederivatives having a carboxamide group at the C6-position of thepyrimidine ring. Carboxylic acid A can be obtained from commercialsources and converted to bromo-dichlorocarboxamide B using a two-stepprocedure. First, carboxylic acid A is treated with thionyl chloride toprovide a dichloro-carboxylic acid intermediate (not shown). Thissynthetic intermediate is subjected to amide coupling conditions in thepresence of an amine compound (HNRR′) to providebromo-dichlorocarboxamide B, which can be converted into the finalproduct in three steps using procedures described in Scheme 1. Exemplaryconditions for performing an amide coupling reaction are described in,for example, “Comprehensive Organic Synthesis” (B. M. Trost & I.Fleming, eds., 1991-1992)

Scheme 5 provides a more detailed exemplary synthetic procedure formaking pyrimidine derivatives having an aryl group at the C6-position ofthe pyrimidine ring. Phenylpyrimidine-dione A can be obtained fromcommercial sources and converted to bromo-pyrimidine-dione B usingbromination conditions described in the literature. See, for example, J.Med. Chem., 1985, 28(12), 1864-1869. Reacting bromo-pyrimidine-dione Bwith phosphorous oxychloride (POCl₃) provides bromo-dichloropyrimidineC, which can be converted to final product D using the proceduresdescribed in Scheme 1 for installing the desired substituents at theC2-position, C4-position, and CS-position of the pyrimidine ring.

III. THERAPEUTIC APPLICATIONS

The invention further provides methods of modulating the activity of oneor more cystic fibrosis transmembrane regulators comprising exposingsaid receptor to a compound of the invention, e.g., a compound ofFormula I, IA, II, IIA, III, or IV, as described herein above. Theinvention further provides methods of treating a disease associated withexpression or activity of one or more cystic fibrosis transmembraneregulators in a patient comprising administering to the patient atherapeutically effective amount of a compound of the invention.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, cysticfibrosis, hereditary emphysema, hereditary hemochromatosis,coagulation-cibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, secretory diarrhea or polycystic kidney disease,mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,myleoperoxidase deficiency, primary hypoparathyroidism, melanoma,glycanosis CDG type 1, hereditary emphysema, congenital hyperthyroidism,osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis, progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders such as Huntington,spinocerebullar ataxia type I, spinal and bulbar muscular atrophy,dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren'sdisease.

One embodiment of the invention provides a method of treating airwayinflammation comprising administering to a subject in need thereof atherapeutically effective amount of a compound of the invention, e.g., acompound of Formula I, IA, II, IIA, III, or IV, as described hereinabove. The methods disclosed herein may involve treating cysticfibrosis.

Another embodiment provides a method of treating cystic fibrosiscomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound described herein, e.g., a compound ofFormula I, IA, II, IIA, III, or IV, as described herein above.

The compounds of the invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician. For treating clinical conditions and diseases noted above,the compound of this invention may be administered orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

Exemplary pharmaceutical compositions of this invention may be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains one or more of the compound ofthe invention, as an active ingredient, in admixture with an organic orinorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual non-toxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

The liquid forms in which the compositions of the invention may beincorporated for administration orally or by injection include aqueoussolution, suitably flavored syrups, aqueous or oil suspensions, andemulsions with acceptable oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, or with a solubilizing or emulsifying agentsuitable for intravenous use, as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin. Compositions forinhalation or insufflation include solutions and suspensions inpharmaceutically acceptable, aqueous or organic solvents, or mixturesthereof, and powders.

Advantageously, the invention also provides kits for use by a consumerhaving, or at risk of having, a disease or condition associated withcystic fibrosis transmembrane regulators. Such kits include a suitabledosage form such as those described above and instructions describingthe method of using such dosage form to mediate, reduce or preventinflammation. The instructions would direct the consumer or medicalpersonnel to administer the dosage form according to administrationmodes known to those skilled in the art. Such kits could advantageouslybe packaged and sold in single or multiple kit units. An example of sucha kit is a so-called blister pack. Blister packs are well known in thepackaging industry and are being widely used for the packaging ofpharmaceutical unit dosage forms (tablets, capsules, and the like).Blister packs generally consist of a sheet of relatively stiff materialcovered with a foil of a preferably transparent plastic material. Duringthe packaging process recesses are formed in the plastic foil. Therecesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

EXAMPLES

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Morespecifically, compounds of the invention may be prepared using thereactions and techniques described herein. In the description of thesynthetic methods described below, it is to be understood that allproposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, can be chosen to be the conditions standard for thatreaction, unless otherwise indicated. It is understood by one skilled inthe art of organic synthesis that the functionality present on variousportions of the molecule should be compatible with the reagents andreactions proposed. Substituents not compatible with the reactionconditions will be apparent to one skilled in the art, and alternatemethods are therefore indicated. The starting materials for the examplesare either commercially available (such as through Aldrich Chemicals Co.(Milwaukee, Wis.), Alfa Aesar (Ward Hill, Mass.), Maybridge ChemicalCompany, Ltd. (Cornwall, England), Ryan Scientific Inc. (Mt. Pleasant,S.C.), Combi-Blocks, Inc. (San Diego, Calif.), and Focus Synthesis LLC(San Diego, Calif.)) or are readily prepared by standard methods fromknown materials.

Unless specified otherwise, starting materials are generally availablefrom commercial sources. NMR spectra were recorded on a Varian AS 400(Varian Inc., Palo Alto, Calif.) at room temperature at 400 MHz forproton, or a Bruker Avance 300 UltraShield™ (Bruker BioSpin Corp.,Billerica, Mass.) at 300 MHz for proton and at 282 MHz for ¹⁹F. Chemicalshifts are expressed in parts per million (δ) relative to residualsolvent as an internal reference. The peak shapes are denoted asfollows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;bs, broad singlet; bd, broad doublet. Liquid chromatography electrosprayionization mass spectra (LCMS) were obtained on an Agilent HP 1100instrument (Agilent Technologies, Foster City, Calif.). Where theintensity of chlorine or bromine-containing ions are described, theexpected intensity ratio was observed (approximately 3:1 for³⁵Cl/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁸¹Br-containing ions) and theintensity of only the lower mass ion is given. MS peaks are reported forall examples. Microwave reactions were performed on a Biotage Emrys™Optimizer (Biotage, Charlottesville, Va.).

Column chromatography was performed on a CombiFlash Companion™ (TeledyneISCO Inc., Lincoln, Nebr.) with different size of RediSep Rf columns.Preparative thin-layer chromatography was performed using Analtechsilica gel GF with UV254 indicator (Analtech Inc., Newark, Del.) on 20cm×20 cm×1 mm plates. When needed, multiple plates are used. Aftereluting the plates with the indicated solvent, the desired band ismarked under UV light, and scraped off. The desired product is extractedfrom the silica using a polar solvent system (e.g., 20% methanol inmethylene chloride or 100% EtOAc). Preparative HPLC was performed on aVarian Dynamax instrument (Varian Inc., Palo Alto, Calif.) using aKromasil 100-10-C18 250 mm×20 mm column (EKA Chemicals, 80 Bohus,Sweden).

Example 1 Preparation ofN,N-dimethyl-3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide

Step 1: Preparation of tert-butyl3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (1)

To a solution of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester(2.5 g, 14.43 mmol) in anhydrous THF (65 mL) was added NaH (55 w/w % inmineral oil, 381 mg, 15.9 mmol) under N₂ atmosphere at 0 to 5° C. Themixture was allowed to warm to room temperature and stirred for 2 hr.Then, this reaction mixture was cooled to −5 to 0° C., and was addedslowly to a solution of 5-bromo-2,4-dichloropyrimidine (3.28 g, 14.43mmol) in anhydrous THF (28 mL) at −5 to 0° C. The mixture was stirred at−5 to 0° C. for 2 hr, then allowed to warm to room temperature andstirred for additional 6 h. After this time, the mixture was quenchedwith water (75 mL) at 0° C. The phases were separated and the aqueousphase was extracted with ethyl acetate (3×50 mL). The organic layerswere combined, dried over anhydrous magnesium sulfate and the solventwas removed under reduced pressure. The residue was purified by columnchromatography (silica gel; eluting with 10% ethyl acetate in hexane) togive the title compound (1) (3.35 g, 64%) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.48 (s, 1H), 5.38-5.46 (m, 1H), 4.38 (dd, J=10.3,6.5 Hz, 2H), 4.06 (dd, J=10.4, 4.1 Hz, 2H), 1.46 (s, 9H); MS (APCI,M+H⁺) C₁₂H₁₆BrClN₃O₃, calcd. 364.0. found 307.9 (M+1-t-butyl), 309.9(M+3-t-butyl)

Step 2: Preparation of tert-butyl3-(5-bromo-2-((1s,4S)-4-methylcyclohexylamino)-pyrimidin-4-yloxy)azetidine-1-carboxylate(2)

To a solution of tert-butyl3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (1) (2.00g, 5.50 mmol) in 15 mL of EtOH was added cis-4-methylcyclohexylaminehydrochloride (1.23 g, 8.23 mmol) followed by triethylamine (1.66 g,2.28 mL, 16.4 mmol). The mixture was heated in a microwave reactor at130° C. for 2 h. After cooling to room temperature, the reaction mixturewas diluted with CH₂Cl₂ (15 mL) and 20 mL of H₂O. The organic layer wasseparated, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel; eluting with 10% ethyl acetate in hexane) to give the titlecompound (2) (1.57 g, 65%) as an off-white solid. ¹H NMR (CDCl₃, 400MHz) δ 8.10 (s, 1H), 5.2-5.33 (m, 1H), 5.16 (bs, 1H), 4.29 (dd, J=10.2,6.9 Hz, 2H), 4.05 (dd, J=10.0, 4.5 Hz, 2H), 3.91 (bs, 1H), 1.68-1.82 (m,2H), 1.53-1.70 (m, 4H), 1.46 (s, 9H), 1.10-1.34 (m, 3H), 0.93 (d, J=6.5Hz, 3H); MS (APCI, M+H⁺) C₁₉H₃₀BrN₄O₃, calcd. 441.1. found 441.2, 443.2.

Step 3: Preparation of tert-butyl3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-carboxylate(3)

To a solution of tert-butyl3-(5-bromo-2-((1s,4S)-4-methylcyclohexylamino)-pyrimidin-4-yloxy)azetidine-1-carboxylate(2) (420 mg, 0.95 mmol) in CH₃CN (16 mL) was added4-(morpholino)phenylboronic acid (394 mg, 1.90 mmol) followed byPd(PPh₃)₄ (110 mg, 0.1 mmol) and aqueous 2M Na₂CO₃ (8 mL). The mixturewas heated in a microwave reactor at 100° C. for 30 minutes. Aftercooling to room temperature, the reaction mixture was diluted with EtOAcand washed with H₂O. The organic layer was separated, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by column chromatography (silica gel, eluting with30% ethyl acetate in hexane) to give the title compound (3) (262 mg,53%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H),7.41 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.27-5.37 (m, 1H), 5.15(bs, 1H), 4.29 (dd, J=9.8, 6.8 Hz, 2H), 4.01 (dd, J=9.9, 4.4 Hz, 3H),3.83-3.91 (m, 4H), 3.13-3.26 (m, 4H), 1.72-1.87 (m, 2H), 1.56-1.72 (m,4H), 1.45 (s, 9H), 1.14-1.34 (m, 3H), 0.94 (d, J=6.3 Hz, 3H); MS (APCI,M+H⁺) C₂₉H₄₂N₅O₄, calcd. 524.3. found 524.4.

Step 4: Preparation of4-(azetidin-3-yloxy)-N-((1s,4S)-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine(4)

tert-Butyl3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-pyrimidin-4-yloxy)azetidine-1-carboxylate(3) (775 mg, 1.48 mmol) was dissolved in 5 mL of 1,4-dioxane saturatedwith HCl gas. The reaction mixture was stirred at room temperature for 2h. After this time, the solvent was removed under reduced pressure, theresidue treated with 5 mL of 20 w/w % aqueous NaHCO₃ and the mixturethen extracted with 2×5 mL of CHCl₃. The combined organic phases weredried over MgSO₄, the drying agent was filtered off and the solvent wasevaporated under reduced pressure to give the title compound (4) (550mg, 87%) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.09 (s, 1H),7.43 (d, J=8.5 Hz, 2H), 6.94 (d, J=8.5 Hz, 2H), 5.49 (qd, J=6.4 Hz, 1H),5.10 (bs, 1H), 3.97-4.09 (m, 1H), 3.83-3.96 (m, 6H), 3.80 (dd, J=9.4,6.4 Hz, 2H), 3.12-3.27 (m, 4H), 1.58-1.90 (m, 8H), 1.16-1.33 (m, 2H),0.94 (d, J=6.3 Hz, 3H); MS (APCI, M+H⁺) C₂₄H₃₄N₅O₂, calcd. 424.2. found424.1.

Step 5: Preparation ofN,N-dimethyl-3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide(5)

To a mixture of4-(azetidin-3-yloxy)-N-((1s,4S)-4-methylcyclohexyl)-5-(4-morpholino-phenyl)pyrimidin-2-amine(4) (90 mg, 0.21 mmol), and Na₂CO₃ (27 mg, 0.25 mmol) in CH₂Cl₂ (5 mL)was added dropwise N,N-dimethylsulfamoyl chloride (76 mg, 0.53 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 30 min. After this time, 5 mL of H₂O was added, the organic layerwas separated and the aqueous phase was extracted with CH₂Cl₂ (2×5 mL).The organic extracts were combined, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by preparative layer chromatography (silica gel, eluting with5% ethanol in methylene chloride) to give the title compound (5) (18 mg,16%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (s, 1H),7.40 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 5.33 (bs, 1H), 5.25 (bs,1H), 4.18-4.25 (m, 2H), 4.07 (dd, J=9.3, 5.3 Hz, 2H), 4.00 (bs, 1H),3.83-3.92 (m, 4H), 3.15-3.26 (m, 4H), 2.82 (s, 6H), 1.73-1.87 (m, 2H),1.55-1.72 (m, 5H), 1.16-1.33 (m, 2H), 0.95 (d, J=6.5 Hz, 3H); MS (APCI,M+H⁺) C₂₆H₃₉N₆O₄S, calcd. 531.2. found 531.3.

Example 2 Preparation of5-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine

Step 1: Preparation of 1-bromo-4-(2-methylallyloxy)benzene (6)

To a solution of 4-bromo phenol (7.0 g, 40.40 mmol) in acetone (165 mL)was added K₂CO₃ (27.8 g, 202 mmol) followed by3-bromo-2-methylprop-1-ene (4.9 mL, 44.5 mmol). The mixture was stirredat reflux temperature for 16 h. After cooling to room temperature, thereaction mixture was diluted with CH₂Cl₂ (200 mL), washed with H₂O (2×50mL) and brine (50 mL). The organic phase was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford the titlecompound (6) (8.0 g, 93%) as a colorless liquid. ¹H NMR (CDCl₃, 400 MHz)δ 7.37 (d, J=9.2 Hz, 2H), 6.81 (d, J=9.2 Hz, 2H), 5.08 (s, 1H), 5.00 (s,1H), 4.41 (s, 2H), 1.83 (s, 3H); MS (ESI, M+H⁺) C₁₀H₁₂BrO, calcd. 227.1.found 227.0, 229.0.

Step 2: Preparation of 4-bromo-2-(2-methylallyl)phenol (7)

A solution of 1-bromo-4-(2-methylallyloxy)benzene (6) (1.0 g, 4.4 mmol)in DMF (8 mL) was heated in a microwave reactor at 190° C. for 2 h.After cooling to room temperature, the reaction mixture was diluted withmethyl tert-butyl ether (50 mL), and washed with H₂O (25 mL), brine (25mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,eluting with 5% ethyl acetate in hexanes) to give the title compound (7)(0.7 g, 65%) as a liquid. ¹H NMR (CDCl₃, 400 MHz) δ 7.27-7.25 (m, 2H),6.72 (d, J=8.4 Hz, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 3.34 (s, 2H), 1.74(s, 3H); MS (ESI, M+H⁺) C₁₀H₁₂BrO, calcd. 227.1. found 227.0, 229.0.

Step 3: Preparation of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (8)

To a solution of 4-bromo-2-(2-methylallyl)phenol (7) (4.5 g, 19.8 mmol)in CH₂Cl₂ (250 mL) was added iodine (1.3 g, 4.95 mmol) and the mixturestirred at room temperature for 48 h. The mixture was then diluted withmethyl tert-butyl ether (100 mL) and washed with H₂O (50 mL), brine (50mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,eluting with 5% ethyl acetate in hexanes) to give the title compound (8)(4.0 g, 88%) as yellow liquid. ¹H NMR (CDCl₃, 400 MHz) δ 7.24 (s, 1H),7.20 (d, J=8.4 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.00 (s, 2H), 1.47 (s,6H); MS (ESI, M+H⁺) C₁₀H₁₂BrO, calcd. 227.1. found 227.0, 229.0.

Step 4: Preparation of2-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(9)

To a solution of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran (8) (4.0 g,17.61 mmol) in 1,4-dioxane (40 mL) was added KOAc (6.0 g, 61.63 mmol)and bis(pinacolato)diboron (4.7 g, 18.49 mmol) followed byPd(dppf)Cl₂.CH₂Cl₂ (1.4 g, 1.76 mmol). The mixture was purged with argonfor 10 min and then heated at reflux temperature for 16 h. After thistime, the mixture was cooled, filtered through a pad of celite and thefiltrate was partitioned between methyl tert-butyl ether (100 mL) andwater (25 mL). The organic phase was separated, washed with brine (25mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography(silica gel, eluting with 5% ethyl acetate in hexanes) to afford thetitle compound (9) (1.0 g, 21%) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.62-7.60 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 3.00 (s, 2H), 1.47 (s,6H), 1.33 (s, 12H); MS (ESI, M+H⁺) C₁₆H₂₄BO₃, calcd. 275.2. found 275.0.

Step 5: Preparation of5-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(10)

To a solution of5-bromo-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(100 mg, 0.28 mmol) in CH₃CN (3 mL) was added2-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(9) (154 mg, 0.56 mmol) followed by Pd(PPh₃)₄ (32 mg, 28 μmol) andaqueous 2M Na₂CO₃ (2.0 mL). The mixture was heated in a microwavereactor at 100° C. for 30 minutes. After cooling to room temperature,the reaction mixture was diluted with EtOAc and washed with H₂O. Theorganic layer was separated, dried (MgSO₄) and concentrated underreduced pressure. The residue was purified by preparative HPLC to givethe title compound (10) (38.2 mg, 32%) as a light brown solid. ¹H NMR(CDCl₃, 400 MHz) δ 8.05 (s, 1H), 7.16-7.24 (m, 2H), 6.73 (d, J=8.0 Hz,1H), 5.53-5.62 (m, 1H), 5.19 (bs, 1H), 4.01-4.13 (m, 2H), 3.83-3.97 (m,3H), 3.04 (s, 2H), 2.19-2.30 (m, 1H), 2.09-2.19 (m, 1H), 1.74-1.88 (m,2H), 1.57-1.72 (m, 5H), 1.50 (s, 6H), 1.18-1.34 (m, 2H), 0.95 (d, J=6.3Hz, 3H); MS (APCI, M+H⁺) C₂₅H₃₄N₃O₃, calcd. 424.3. found 424.3.

Example 3 Preparation of5-(3-methylbenzo[d]isoxazol-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine

Step 1: Preparation of (E)-1-(5-bromo-2-hydroxyphenyl)ethanone oxime(11)

To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.30 mmol)in ethanol (20 mL) were added hydroxylamine hydrochloride (0.7 g, 10.2mmol) and potassium acetate (1.0 g, 10.2 mmol). The mixture was stirredat reflux temperature for 16 h. After this time, the mixture was cooled,concentrated and the residue was diluted with CH₂Cl₂ (25 mL) and washedwith H₂O (25 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford title compound(11) (2.1 g, 95%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.40 (s,1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 2.50 (bs,1H), 2.20 (s, 3H); MS (ESI, M+H⁺) C₈H₉BrNO₂, calcd. 230.0. found 230.0,232.0.

Step 2: Preparation of 5-bromo-3-methylbenzo[d]isoxazole (12)

To a stirred solution of triphenylphosphine (6.8 g, 26.1 mmol) and2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (3.9 g, 26.1 mmol) in CH₂Cl₂(50 mL) was added (E)-1-(5-bromo-2-hydroxyphenyl)ethanone oxime (11)(5.0 g, 21.73 mmol) in small portions over a period of 15 min. Themixture was stirred for additional 10 min at room temperature and thenthe solvent was removed under reduced pressure. The residue was purifiedby flash column chromatography (silica gel, eluting with 5% ethylacetate and hexanes) to give the title compound (12) (3.0 g, 65%) as abrown solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.79 (s, 1H), 7.40 (dd, J=8.4,1.6 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 2.64 (s, 3H); MS (ESI, M+H⁺)C₈H₇BrNO, calcd. 212.0. found 212.0, 214.0.

Step 3: Preparation of3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole (13)

To a solution of 5-bromo-3-methylbenzo[d]isoxazole (12) (3.0 g, 14.14mmol) in 1,4-dioxane (30 mL) were added KOAc (4.8 g, 49.40 mmol) andbis(pinacolato)diboron (3.7 g, 14.84 mmol) followed by Pd(dppf)Cl₂ (1.1g, 1.41 mmol). The mixture was purged with argon for 10 min and thenstirred at reflux temperature for 2 h. After this time, the mixture wascooled, filtered through a pad of celite and the filtrate waspartitioned between methyl tert-butyl ether (100 mL) and H₂O (25 mL).The organic phase was separated and washed with brine (25 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by flash chromatography (silica gel, elutingwith 5% ethyl acetate in hexanes) to yield the title compound (13) (1.4g, 38%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.09 (s, 1H), 7.76(d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 2.65 (s, 3H), 1.37 (s, 12H);MS (ESI, M+H⁺) C₁₄H₁₉BNO₃, calcd. 260.1. found 259.9.

Step 4: Preparation of5-(3-methylbenzo[d]isoxazol-5-yl)-N-((1s,4S)-4-methyl-cyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(14)

To a solution of5-bromo-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(100 mg, 0.28 mmol) in CH₃CN (3 mL) was added3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]isoxazole(13) (145 mg, 0.56 mmol) followed by Pd(PPh₃)₄ (32 mg, 28 mmol) andaqueous 2M Na₂CO₃ (2.0 mL). The mixture was heated in a microwavereactor at 100° C. for 30 minutes. After cooling to room temperature,the mixture was diluted with EtOAc and washed with H₂O. The organiclayer was separated, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by preparative HPLC to give the titlecompound (14) (44 mg, 39%) as an off-white solid. ¹H NMR (CDCl₃, 400MHz) δ 8.12 (s, 1H), 7.73 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.37 (dd,J=8.5, 1.5 Hz, 1H), 5.55-5.66 (m, 1H), 5.23 (bs, 1H), 4.02-4.16 (m, 2H),3.82-3.95 (m, 3H), 2.65 (s, 3H), 2.19-2.29 (m, 2H), 2.09-2.19 (m, 1H),1.75-1.90 (m, 2H), 1.55-1.74 (m, 5H), 1.17-1.35 (m, 2H), 0.95 (d, J=6.3Hz, 2H); MS (APCI, M+H⁺) C₂₃H₂₉N₄O₃, calcd. 409.2. found 409.3.

Example 4 Preparation ofN,N-dimethyl-3-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxamide

Step 1: Preparation of tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate(15)

To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.9 g,5.02 mmol) in anhydrous pyridine (10 mL) at 0° C. was added4-methylbenzene-1-sulfonyl chloride (1.0 g, 5.27 mmol). The suspensionwas allowed to warm to room temperature and stirred for 24 h. After thistime, the suspension was poured onto crushed ice and extracted withEtOAc. The organic layer was separated, washed with water, brine, dried(MgSO₄) and concentrated under reduced pressure to give the titlecompound (15) (1.1 g, 69%) as a light yellow colored solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.79 (d, J=8.3 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H),4.94-5.17 (m, 1H), 3.33-3.56 (m, 4H), 2.46 (s, 3H), 1.79-2.28 (m, 2H),1.43 (s, 9H); MS (APCI, M+H⁺) C₁₆H₂₄NO₅S, calcd. 342.1. found 286.1.

Step 2: Preparation of4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenol(16)

To a solution of5-bromo-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(700 mg, 1.96 mmol) in CH₃CN (28 mL) was added 4-hydroxyphenylboronicacid (542 mg, 3.93 mmol) followed by Pd(PPh₃)₄ (113 mg, 98 μmol) andaqueous 2M Na₂CO₃ (14 mL). The mixture was heated in a microwave reactorat 100° C. for 30 minutes. After cooling to room temperature, thereaction mixture was diluted with EtOAc and washed with H₂O. The organiclayer was separated, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel,eluting with 30% ethyl acetate in hexane) to give the title compound(16) (602 mg, 83%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.07 (s,1H), 7.33 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.56-5.62 (m, 1H),5.66 (bs, 1H), 5.20 (bs, 1H), 4.08 (dd, J=10.1, 5.2 Hz, 1H), 3.99-4.12(m, 1H), 3.85-3.98 (m, 3H), 2.09-2.29 (m, 2H), 1.75-1.87 (m, 2H),1.56-1.71 (m, 5H), 1.17-1.32 (m, 2H), 0.94 (d, J=6.5 Hz, 3H); MS (APCI,M+H⁺) C₂₁H₂₈N₃O₃, calcd. 370.2. found 370.2.

Step 3: Preparation of tert-butyl3-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxylate(17)

To a solution of4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenol(16) (100 mg, 0.27 mmol) in anhydrous CH₃CN (2 mL) was added potassiumcarbonate (45 mg, 0.33 mmol) followed by tert-butyl3-(tosyloxy)pyrrolidine-1-carboxylate (15) (111 mg, 0.32 mmol). Theresulting mixture was stirred at reflux temperature for 62 h. After thistime, the suspension was cooled, poured into cold water and extractedwith EtOAc. The organic layer was separated, dried (MgSO₄) andconcentrated under reduced pressure. The residue was purified bypreparative HPLC to give the title compound (17) (86 mg, 59%) as a whitesolid. ¹H NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H), 7.38 (bs, 2H), 6.88 (d,J=8.8 Hz, 2H), 5.59 (bs, 1H), 5.19 (bs, 1H), 4.90 (bs, 1H), 4.08 (dd,J=10.1, 5.1 Hz, 1H), 4.02-4.12 (m, 1H), 3.83-3.96 (m, 3H), 3.45-3.72 (m,4H), 2.02-2.29 (m, 4H), 1.76-1.89 (m, 2H), 1.54-1.72 (m, 5H), 1.47 (s,9H), 1.18-1.34 (m, 2H), 0.95 (d, J=6.3 Hz, 3H); MS (APCI, M+H⁺)C₃₀H₄₃N₄O₅, calcd. 539.3. found 539.4.

Step 4: Preparation ofN-((1s,4S)-4-methylcyclohexyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(18)

To a solution of tert-butyl3-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxylate(17) (207 mg, 0.38 mmol) in anhydrous dichloromethane (1 mL) was addedtrifluoroacetic acid (TFA) (1 mL). The resulting mixture was stirred for1 h at room temperature. After this time, the mixture was concentratedunder reduced pressure. The residue was dissolved in dichloromethane andwashed with saturated aqueous NaHCO₃. The organic extract wasconcentrated under reduced pressure. The residue was purified bypreparative HPLC and then again by preparative layer chromatography(silica gel, eluting with 17% methanol in chloroform) to give the titlecompound (18) (148 mg, 88%) as a light brown solid. ¹H NMR (CDCl₃, 400MHz) δ 8.08 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H),5.54-5.64 (m, 1H), 5.08-5.22 (m, 1H), 4.87 (t, J=5.0 Hz, 1H), 4.00-4.14(m, 2H), 3.83-3.97 (m, 3H), 3.17-3.32 (m, 2H), 3.11 (dd, J=12.5, 4.8 Hz,1H), 2.96-3.06 (m, 1H), 1.97-2.29 (m, 4H), 1.74-1.91 (m, 2H), 1.58-1.73(m, 5H), 1.15-1.35 (m, 2H), 0.95 (d, J=6.5 Hz, 3H); MS (APCI, M+H⁺)C₂₅H₃₅N₄O₃, calcd. 439.3. found 439.4.

Step 5: Preparation ofN,N-dimethyl-3-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxamide(19)

To a mixture ofN-((1S,4S)-4-methylcyclohexyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(18) (70 mg, 0.16 mmol) and saturated aqueous Na₂CO₃ (2 mL) indichloromethane (5 mL) was added dropwise N,N-dimethylcarbamyl chloride(111 mg, 1.04 mmol). The resulting mixture was stirred for 1 hr at roomtemperature. After this time, the organic layer was separated and theaqueous phase was extracted with dichloromethane (2×5 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by preparative thin layerchromatography (silica gel, eluting with 3% methanol in chloroform) togive the title compound (19) (35 mg, 43%) as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.38 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H),5.53-5.65 (m, 1H), 5.28 (bs, 1H), 4.84-4.96 (m, 1H), 3.99-4.18 (m, 2H),3.78-3.99 (m, 4H), 3.59-3.73 (m, 1H), 3.43-3.57 (m, 2H), 2.86 (s, 6H),1.99-2.33 (m, 4H), 1.74-1.89 (m, 2H), 1.56-1.73 (m, 5H), 1.17-1.36 (m,2H), 0.95 (d, J=6.5 Hz, 3H); MS (APCI, M+H⁺) C₂₈H₄₀N₅O₄, calcd. 510.3.found 510.4.

Example 5 Preparation ofN-((1s,4S)-4-methylcyclohexyl)-5-(4-(1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine

To a mixture ofN-((1s,4S)-4-methylcyclohexyl)-5-(4-(pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine(18) (70 mg, 0.16 mmol) and saturated aqueous Na₂CO₃ (2 mL) indichloromethane (5 mL) was added dropwise methanesulfonyl chloride (118mg, 1.04 mmol). The resulting mixture was stirred for 1 h at roomtemperature. After this time, the organic layer was separated and theaqueous phase was extracted with dichloromethane (2×5 mL). The organicextracts were combined, dried (MgSO₄) and concentrated under reducedpressure. The residue was purified by preparative thin layerchromatography (silica gel, eluting with 3% methanol in chloroform) andthen again by preparative HPLC to give the title compound (20) (18 mg,22%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H), 7.40 (d,J=8.5 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.60 (t, J=5.6 Hz, 1H), 5.17 (bs,1H), 4.95 (t, J=4.0 Hz, 1H), 4.00-4.12 (m, 2H), 3.83-3.97 (m, 3H),3.55-3.72 (m, 3H), 3.41-3.54 (m, 1H), 2.86 (s, 3H), 2.30-2.40 (m, 1H),2.07-2.30 (m, 3H), 1.75-1.88 (m, 2H), 1.57-1.74 (m, 5H), 1.18-1.33 (m,2H), 0.95 (d, J=6.3 Hz, 3H); MS (APCI, M+H⁺) C₂₆H₃₇N₄O₅S, calcd. 517.2.found 517.2.

Example 6 Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride salt

Step 1: Preparation of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a mixture of (R)-tetrahydrofuran-3-ol (1 g, 11.4 mmole) and TEA (2.3g, 22.8 mmole) in DCM (20 mL) at 0° C. was added dropwise4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resultingmixture was stirred at room temperature for 8 h. The mixture was washedwith water, dried over MgSO₄, filtered, and concentrated. The crudeproduct was purified by ISCO (silica gel, eluting with 15% ethyl acetatein hexane) to give the title compound (2.3 g). MS (ESI) m/z: Found:243.3 (M⁺+1). Calc. 242.3 (M⁺).

Step 2: Preparation of (S)-3-(4-bromophenoxy)-tetrahydrofuran

A mixture of 4-bromophenol (1.8 g, 10.5 mmole), (R)-tetrahydrofuran-3-yl4-methylbenzenesulfonate (2.3 g, 9.5 mmole) and K₂CO₃ (4.0 g, 29 mmole)in DMF (15 mL) was heated at 85° C. for 15 h. The reaction mixture wasdiluted with ethyl acetate, washed with water, dried over MgSO₄,filtered, and concentrated under vacuum. The crude product was purifiedby ISCO (silica gel, eluting with 5% ethyl acetate in hexane) to givethe title compound (690 mg). MS (ESI) m/z: Found: 244.3 (M⁺+1). Calc.243.1 (M⁺).

Step 3: Preparation of2-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a mixture of (S)-3-(4-bromophenoxy)-tetrahydrofuran (690 mg, 2.84mmol), bis(pinacolato)diboron (779.4 mg, 3.07 mmol), potassium acetate(834 mg, 8.5 mmol) and palladium acetate (21.8 mg, 0.087 mmol) in dryDMF (5 mL) was purged with N₂ gas for 30 min. The reaction mixture washeated at 85° C. for 9 h. The resulting mixture was partitioned betweenwater (15 mL) and ethyl acetate (20 mL). The aqueous layer was extractedwith ethyl acetate (20 mL). The combined ethyl acetate layers was driedover magnesium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified by ISCO (silica gel, eluting with 5 to 10% ethylacetate in hexane) to give the title compound (640 mg, 77% yield). ¹HNMR (CDCl₃, 400 MHz): δ 7.76 (d, 2H), 6.86 (d, 2H), 4.98-4.96 (m, 1H),4.03-3.88 (m, 4H), 2.24-2.15 (m, 2H), 1.34 (s, 12H); MS (ESI) m/z:Found: 291.1 (M⁺+1). Calc. 290.2 (M⁺).

Step 4: Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine

Using the procedure of Example 1, Step 3,4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminewas reacted with2-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneto provide the title compound as a free base.

Example 7 Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride salt

Step 1: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) andtriethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL)at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4mmole). The resulting mixture was stirred at room temperature for 8 h.The mixture was washed with water, dried over MgSO₄, filtered, andconcentrated. The crude product was purified by ISCO (silica gel, 15%ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI)m/z: Found: 243.3 (M⁺+1). Calc. 242.3 (M⁺).

Step 2: Preparation of (R)-3-(4-bromophenoxy)-tetrahydrofuran

A mixture of 4-bromophenol (2.1 g, 12.4 mmole), (S)-tetrahydrofuran-3-yl4-methylbenzenesulfonate (2.5 g, 10.3 mmole) and K₂CO₃ (4.3 g, 30.9mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The mixture wasdiluted with ethyl acetate, washed with water, dried over MgSO₄,filtered, and concentrated under vacuum. The crude product was purifiedby ISCO (silica gel, elute: 5% ethyl acetate in hexane) to give thetitle compound (896 mg). MS (ESI) m/z: Found: 244.3 (M⁺+1). Calc. 243.1(M⁺).

Step 3: Preparation of2-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirring solution of (R)-3-(4-bromophenoxy)-tetrahydrofuran (896mg, 3.1 mmole), bis(pinacolato)diboron (850 mg, 3.35 mmole), potassiumacetate (913 mg, 9.3 mmole) and palladium acetate (23.3 mg, 0.093 mmole)in dry DMF (5 mL) was purged with N₂ gas for 10 min. The mixture wasthen heated at 85° C. for 9 h. The resulting mixture was partitionedbetween water (15 mL) and ethyl acetate (20 mL). The aqueous solutionwas extracted with ethyl acetate (20 mL). The combined ethyl acetateextracts were dried over magnesium sulfate, filtered and concentrated invacuo. The crude product was purified by ISCO (silica gel, eluting with5 to 10% ethyl acetate in hexane) to give the titled compound (665 mg).¹H NMR (CDCl₃, 300 MHz): δ 7.79 (d, 2H), 6.89 (d, 2H), 5.02 (m, 1H),4.06-4.02 (m, 4H), 2.26-2.21 (m, 2H), 1.38 (s, 12H); MS (ESI) m/z:Found: 291.1 (M⁺+1). Calc. 290.2 (M⁺).

Step 4: Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 3,3,4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminewas reacted with2-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneto provide the title compound.

Example 8 Preparation of (R)-methyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate

Step 1: Preparation of (R)-tert-butyl3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate

Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidinewas reacted with (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate to provide the titlecompound. ¹H NMR (CDCl₃, 400 MHz) δ 8.42 (s, 1H), 4.10 (m, 2H),3.62-3.17 (m, 5H), 2.72-2.69 (m, 1H), 2.10-2.05 (m, 2H), 1.80-1.75 (m,1H), 1.44 (s, 9H); MS (ESI) m/z: Calc: 392.68 (M). Found. 337.9(M⁺-(CH₃)₃C).

Step 2: Preparation of (R)-tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate

Using the procedure of Example 1 Step 2, (R)-tert-butyl3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylatewas reacted with cis-4-methylcyclohexanamine to provide the titlecompound at 55% yield. ¹H NMR (CDCl₃, 400 MHz) δ 8.06 (s, 1H), 5.13 (sb,1H), 4.28 (m, 2H), 3.96 (m, 1H), 3.60-3.15 (m, 4H), 2.66 (m, 1H), 2.02(m, 1H), 1.77-1.58 (m, 7H), 1.44 (s, 9H), 1.28-1.16 (m, 3H), 0.91 (d,3H); MS (ESI) m/z: Calc: 544.2 (M⁺). Found. 545.2 (M⁺1).

Step 3: Preparation of (R)-tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate

Using the procedure of Example 1 Step 3, (R)-tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylatewith 4-morpholinophenylboronic acid to provide the title compound at 85%yield. ¹H NMR (CDCl₃, 400 MHz) δ 8.05 (s, 1H), 7.36 (d, 2H), 6.92 (d,2H), 5.16 (sb, 1H), 4.30-4.27 (m, 2H), 4.10-4.01 (m, 1H), 386-3.84 (m,4H), 3.60-3.12 (m, 8H); 2.70-2.62 (m, 1H), 2.05-1.98 (m, 1H), 1.81-1.46(m, 8H), 1.44 (s, 9H), 1.29-1.21 (m, 3H), 0.93 (d, 3H); MS (ESI) m/z:Found: 552.3 (M⁺1); Calc: 551.4 (M⁺).

Step 4: Preparation of4-(((R)-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 4, (R)-tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylatewas deprotected by TFA to provide the title compound at quantitativeyield. MS (ESI) m/z: Found: 452.3 (M⁺1). Calc. 451.3 (M⁺).

Step 5: Preparation of (R)-methyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylatehydrochloride salt

Using the procedure of Example 1 Step 5,4-(((R)-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewith methyl chloroformate to provide the title compound. ¹H NMR (CDCl₃,400 MHz) δ 8.08 (s, 1H), 7.38 (d, 2H), 6.94 (d, 2H), 5.22 (sb, 1H), 4.31(d, 2H), 4.07 (m, 1H), 3.88 (m, 4H), 3.70 (s, 3H), 3.72-3.36 (m, 4H),2.68 (m, 1H), 2.03 (m, 2H), 1.87-1.52 (m, 6H), 1.25 (m, 3H), 0.95 (d,3H); MS (ESI) m/z: Found: 510.3 (M⁺1). Calc. 509.3 (M⁺).

Example 9 Preparation of4-(((R)-1-methylsulfonyl-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 5,4-(((R)-pyrrolidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewith methanesulfonyl chloride to provide the title compound in 67%yield. ¹H NMR (CDCl₃, 400 MHz) δ 8.03 (s, 1H), 7.33 (d, 2H), 6.94 (d,2H), 5.40 (sb, 1H), 4.35 (m, 2H), 4.08 (m, 1H), 3.88 (m, 4H), 3.55-3.31(m, 4H), 3.18 (m, 4H), 2.76 (s, 3H), 2.17-2.10 (m, 1H), 1.86-1.25 (m,9H), 0.95 (d, 3H); MS (ESI) m/z: Found: 530.3 (M⁺1). Calc. 529.3 (M⁺).

Example 10 Preparation of Methyl3-((2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate

Step 1: Preparation of tert-butyl3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)azetidine-1-carboxylate

Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidinewas reacted with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate toprovide the title compound at 67% yield. ¹H NMR (CDCl₃, 400 MHz) 8.46(s, 1H), 4.61 (d, 2H), 4.10 (m, 2H), 3.82 (m, 2H), 3.03 (m, 1H), 1.45(9H); MS (ESI) m/z: Calc: 377.0 (M⁺). Found. 322.9 (M⁺-(CH₃)₃C+1).

Step 2: Preparation of tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)azetidine-1-carboxylate

Using the procedure of Example 1 Step 2, tert-butyl3-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)azetidine-1-carboxylate wasreacted with cis-4-methylcyclohexanamine to provide the title compoundin 55% yield. ¹H NMR (CDCl₃, 300 MHz) 8.10 (s, 1H), 5.17 (m, 1H), 5.47(d, 2H), 4.11-4.00 (m, 3H), 3.84-3.79 (m, 2H), 3.02-2.98 (m, 1H),1.78-1.58 (m, 6H), 1.46 (s, 9H), 1.46-1.27 (m, 3H), 0.95 (d, 3H); MS(ESI) m/z: Calc: 454.2 (M⁺). Found. 456.1 (M⁺2).

Step 3: Preparation of tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate

Using the procedure of Example 1 Step 3, tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)azetidine-1-carboxylatewas reacted with 4-morpholinophenylboronic acid to provide the titlecompound at 78% yield. ¹H NMR (CDCl₃, 400 MHz) 8.02 (s, 1H), 7.30 (d,2H), 6.85 (d, 2H), 5.38 (sb, 1H), 4.41 (d, 2H), 4.07-3.80 (m, 3H),4.79-3.70 (m, 5H), 3.11-3.09 (m, 4H), 2.95-2.88 (m, 2H), 1.76-1.45 (m,6H), 1.44 (s, 9H), 1.20-1.16 (m, 3H), 0.87 (d, 3H); MS (ESI) m/z: Calc:537.3 (M⁺). Found. 538.3 (M⁺1).

Step 4: Preparation of4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 4, tert-butyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylatewas deprotected by TFA to provide the title compound at quantitativeyield. ¹H NMR (CDCl₃, 400 MHz) 8.02 (s, 1H), 7.32 (d, 2H), 6.87 (d, 2H),5.24 (sb, 1H), 4.42 (d, 2H), 4.05 (m, 1H), 3.82-3.80 (m, 4H), 3.65 (m,2H), 3.50 (m, 2H), 3.14-3.11 (m, 4H), 3.05 (bs 1H), 3.03-2.97 (m, 1H),1.79-1.48 (m, 6H), 1.23-1.18 (m, 3H), 0.88 (d, 3H); MS (ESI) m/z: Calc:437.3 (M⁺). Found. 438.3 (M⁺1).

Step 5: Preparation of methyl3-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate

Using the procedure of Example 1 Step 5,4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewas reacted with methyl chloroformate to provide the title compound at83% yield. ¹H NMR (CDCl₃, 400 MHz) 8.10 (s, 1H), 7.35 (d, 2H), 6.92 (d,2H), 5.16 (sb, 1H), 4.47 (d, 2H), 4.12-4.08 (m, 3H), 3.88-3.84 (m, 6H),3.67 (s, 3H), 3.20-3.18 (m, 4H), 3.10-2.90 (m, 1H), 1.85-1.52 (m, 6H),1.30-1.20 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 495.3 (M⁺). Found.496.3 (M⁺1).

Example 11 Preparation of4-((1-methylsulfonyl-azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 5,4-((azetidin-3-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewas reacted with methanesulfonyl chloride to provide the title compoundin 87% yield. ¹H NMR (CDCl₃, 400 MHz) 8.09 (s, 1H), 7.34 (d, 2H), 6.93(d, 2H), 5.17 (sb, 1H), 4.50 (d, 2H), 4.08 (m, 1H), 4.01 (m, 2H), 3.87(m, 4H), 3.82 (m, 2H), 3.17 (m, 4H), 3.05 (m, 1H), 2.66 (s, 3H),1.85-1.55 (m, 6H), 1.80-1.40 (m, 3H), 0.94 (d, 3H); MS (ESI) m/z: Calc:515.3 (M). Found. 516.3 (M⁺1).

Example 12 Preparation of methyl4-((2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate

Step 1: Preparation of tert-butyl4-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)piperidine-1-carboxylate

Using the procedure of Example 1 Step 1, 5-bromo-2,4-dichloropyrimidinewas reacted with tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate toprovide the title compound in 63% yield. ¹H NMR (CDCl₃, 400 MHz) 8.43(s, 1H), 4.32 (d, 2H), 4.18 (m, 2H), 2.76 (m, 2H), 2.03 9 m, 1H), 1.80(m, 2H), 1.46 (s, 9H), 1.34-1.26 (m, 2H); MS (ESI) m/z: Calc: 405.1(M⁺). Found. 307.9 (M⁺-Boc+2).

Step 2: Preparation of tert-butyl4-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)piperidine-1-carboxylate

Using the procedure of Example 1 Step 2 tert-butyl4-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)piperidine-1-carboxylatewas reacted with cis-4-methylcyclohexanamine to provide the titlecompound in 50% yield. ¹H NMR (CDCl₃, 400 MHz) 8.05 (s, 1H), 5.10 (sb,1H), 4.15 (m, 4H), 3.96 (m, 1H), 2.71 (m, 2H), 1.95 (m, 1H), 1.78-1.48(m, 9H), 1.44 (s, 9H), 1.28-1.16 (m, 3H), 0.91 (d, 3H); MS (ESI) m/z:Calc: 482.2 (M⁺). Found. 484.2 (M⁺+2).

Step 3: Preparation of tert-butyl4-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate

Using the procedure of Example 1 Step 3, tert-butyl4-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)piperidine-1-carboxylatewas reacted with 4-morpholinophenylboronic acid to provide the titlecompound at 70% yield. ¹H NMR (CDCl₃, 400 MHz) 8.03 (s, 1H), 7.35 (d,2H), 6.89 (d, 2H), 5.17 (sb, 1H), 4.16-4.03 (m, 6H), 3.83 (m, 4H), 3.15(m, 4H), 2.66 (m, 2H), 1.91-1.44 (m, 11H), 1.41 (s, 9H), 0.95 (d, 3H);MS (ESI) m/z: Calc: 565.4 (M⁺). Found. 566.3 (M⁺1).

Step 4: Preparation of4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 4, tert-butyl4-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylatewas deprotected by TFA to provide the title compound. MS (ESI) m/z:Calc: 465.3 (M⁺). Found. 466.3 (M⁺1).

Step 5: Preparation of methyl4-((2-(cis-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate

Using the procedure of Example 1 Step 5,4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewas reacted with methyl chloroformate to provide the title compound. ¹HNMR (CDCl₃, 400 MHz) 8.07 (s, 1H), 7.37 (d, 2H), 6.93 (d, 2H), 5.19 (sb,1H), 4.19 (d, 2H), 4.07 (m, 3H), 3.88 (m, 4H), 3.69 (s, 3H), 3.20 (m,4H), 2.77 (m, 2H), 1.97-1.57 (m, 11H), 1.26 (m, 3H), 0.94 (d, 3H); MS(ESI) m/z: Calc: 523.3 (M⁺). Found. 524.3 (M⁺1).

Example 13 Preparation of4-((1-methylsulfonyl-piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 5,4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-aminewas reacted with methanesulfonyl chloride to provide the title compoundat 86% yield. ¹H NMR (CDCl₃, 400 MHz) 8.07 (s, 1H), 7.36 (d, 2H), 6.93(d, 2 h), 5.20 (s, 1H), 4.23 (d, 2H), 4.07 (m, 1H), 3.89-3.83 (m, 6H),3.21-3.18 (m, 4H), 2.76 (s, 3H), 2.67 (m, 2H), 1.90-1.24 (m, 14H), 0.94(d, 3H); MS (ESI) m/z: Calc: 543.3 (M⁺). Found. 544.3 (M⁺1).

Example 14 Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethyl)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride

Step 1: Preparation of 1-bromo-4-(2-methoxyethyl)benzene

To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in anhydrous THF(10 mL) was added NaH (60% oil dispersion, 0.2 g, 5 mmol). The mixturewas stirred at room temperature for 30 min and cooled to −0° C.Iodomethane (920 mg, 6.5 mmole) was added slowly to the mixture andstirred for 8 h. The reaction mixture was then quenched by adding water,extracted with ethyl acetate. The combined organic extracts were driedover MgSO₄, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 5% ethyl acetate in hexane) to givethe title compound as a colorless (1 g, 93% yield). ¹H NMR (CDCl₃, 400MHz): 7.39 (d, 2H), 7.08 (d, 2H), 3.56 (t, 2H), 3.33 (s, 3H), 2.82 (t,2H); MS (ESI) m/z. Calc. 215.1 (M⁺). Found: 216.3 (M′+1), 218.1 (M⁺+3).

Step 2: Preparation of 4-(2-methoxyethyl)phenylboronic acid

To a solution of 1-bromo-4-(2-methoxyethyl)benzene (1 g, 4.6 mmole) inTHF (15 mL) at −78° C. was added dropwise BuLi (2.5M in hexane) (2.4 mL,6 mmole). After stirring at −78° C. for 20 min, trimethyl borate (0.62g, 6 mmole) was added to the mixture at −78° C. The mixture was slowlywarmed to room temperature and stirred at room temperature for 1 h. 2NHCl was added to the reaction mixture and stirred for 2 h. The mixturewas extracted with ether, washed with water, dried over MgSO₄, andfiltered. Hexane was added to the ether solution. Solid was precipitatedand collected by filtration. The solid was used in the next step withoutpurification. MS (ESI) m/z: Calc: 180.0 (M⁺). Found: 181.3 (M⁺+1).

Step 3: Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethyl)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride

The title compound was prepared according methods used for preparing forExample 1. Using the procedure of Example 1 Step 3,4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminewas reacted with 4-(2-methoxyethyl)phenylboronic acid to provide thetitle compound as a free base in 85% yield. ¹H NMR (CDCl₃, 400 MHz) 9.11(d, 1H), 7.74 (s, 1H), 7.27-7.24 (m, 4H), 5.65-5.63 (m, 1H), 4.12-4.09(m, 1H), 4.06-3.88 (m, 4H), 3.62 (t, 2H), 3.35 (s, 3H), 2.90 (t, 2H),2.30-2.15 (m, 2), 1.85-1.80 (m, 2H), 1.65-1.46 (m, 9H), 0.97 (d, 3H). MS(ESI) m/z: Calc. 411.3 (M). Found: 412.3 (M⁺+1). The free base compoundwas treated with HCl (2M in ether) to provide the title compound.

Example 15 Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethoxy)phenyl)-N-((1S,4S)-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride

Step 1: Preparation of2-(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g,4.5 mmole), 1-bromo-2-methoxyethane (0.7 g, 5 mmole) and K₂CO₃ (1.3 g, 9mmole) in DMF (10 mL) was heated at 85° C. for 20 hr, diluted by ethylacetate, washed by water, dried over MgSO₄, filtered, concentrated undervacuum, purified by ISCO (silica gel, elute: 10% ethyl acetate inhexane) to give liquid product (316 mg, 25% yield). MS (ESI) m/z: Calc.278.2 (M⁺). Found: 279.3 (M⁺+1).

Step 2: Preparation of4-((R)-tetrahydrofuran-3-yloxy)-5-(4-(2-methoxyethoxy)phenyl)-N-((1S,4S)-4-methylcyclohexyl)pyrimidin-2-aminehydrochloride

Using the procedure of Example 1 Step 3,4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminewas reacted with2-(4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane toprovide the title compound as the free base at 75% yield. ¹H NMR (CDCl₃,400 MHz) 9.01 (d, 1H), 7.35 (s, 1H), 7.19 (d, 2H), 6.90 (d, 2H),5.56-5.38 (m, 1H), 4.07-3.67 (m, 8H), 3.37 (s, 1H), 2.24-2.05 (m, 2H),1.80-1.78 (m 2H), 1.61-1.37 (m, 9H), 0.91 (d, 3H). MS (ESI) m/z: Calc.427.3 (M⁺). Found: 428.3 (M⁺+1). The free base compound was treated withHCl (2M in ether) to provide the title compound.

Example 16 Preparation of4-((R)-tetrahydrofuran-3-yloxy)-N-((1S,4S)-4-methylcyclohexyl)-5-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)pyrimidin-2-aminehydrochloride

Step 1: Preparation of tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate

To tetrahydro-2H-pyran-4-ol (1 g, 9.8 mmole) and TEA (2 g, 19.6 mmole)in DCM (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (1.8 g, 9.8mmole) at 0° C. The mixture was stirred at room temperature for 8 h,washed with water, dried over MgSO₄, filtered, and concentrated. Theresidue was purified by ISCO (silica gel, 15% ethyl acetate in hexane)to give the title compound (2.2 g, 89% yield) as white solid. MS (ESI)m/z: Found: 257.3 (M⁺+1). Calc. 256.3 (M).

Step 2: Preparation of4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolane

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g,4.5 mmole), tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (1.4 g,5.4 mmole) and K₂CO₃ (1.3 g, 9 mmole) in DMF (10 mL) was heated at 85°C. for 20 h. The mixture was diluted with ethyl acetate, washed withwater, dried over MgSO₄, filtered, and concentrated under vacuum. Theresidue was purified by ISCO (silica gel, elute: 10% ethyl acetate inhexane) to give the title compound (335 mg, 24% yield) as a solid. MS(ESI) m/z: Calc. 304.2 (M⁺). Found: 305.3 (M⁺+1).

Step 3: Preparation of4-((R)-tetrahydrofuran-3-yloxy)-N-((1s,4S)-4-methylcyclohexyl)-5-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)pyrimidin-2-aminehydrochloride

Using the procedure of Example 1 Step 3,4-((R)-tetrahydrofuran-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-aminewas reacted with4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-1,3,2-dioxaborolaneto provide the title compound as a free base at 87% yield. ¹H NMR(CDCl₃, 300 MHz) 9.08 (d, 1H), 7.74 (s, 1H), 7.27 (d, 2H), 6.97 (d, 2H),5.67-5.64 (m, 1H), 4.55-4.51 (m, 1H), 4.13-3.94 (m, 7H), 3.98-3.59 (m,2H), 2.31-1.49 (m, 15H), 0.98 (d, 3H). MS (ESI) m/z: Calc. 453.3 (M⁺).Found: 454.3 (M⁺1). The free base compound was treated with HCl (2M inether) to provide the title compound.

Example 17 Preparation ofN-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)-azetidin-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Step 1: Preparation of tert-butyl3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.1 g,23.7 mmole) in anhydrous THF (100 mL) at 0° C. was added NaH (60% inmineral oil, 1.33 g, 33.2 mmol). The mixture was stirred at 0° C. for 45 min and then room temperature for 2 h until there was no hydrogenbubbles generated. This mixture was added slowly to a solution of5-bromo-2,4-dichloropyrimidine (10.8 g, 47.4 mmol) in THF (100 mL) at−20° C., and then the reaction mixture was stirred at the sametemperature for 2 h and then at room temperature for 3 h. The reactionwas quenched with water and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified using flash chromatography (silica gel, 5-10% EtOAc in hexanes)to give the title compound (6 g, 70% yield) as a white solid. MS (ESI)m/z: Calc. 363.0 (M⁺). Found: 309.1 (M⁺+2-tButyl).

Step 2: Preparation of tert-Butyl3-(5-bromo-2-(cis-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate

A mixture of tert-butyl3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (6 g, 16.4mmol), cis-4-methylcyclohexanamine hydrochloride (2.4 5g, 16.4 mmol) andEt₃N (7 mL, 49.2 mmol) in EtOH (20 mL) was executed in microwave reactorat 130° C. for 2 h. The resulting mixture was concentrated under vacuum.The residue was purified by flash chromatography (silica gel, eluted by10 to 20% ethyl acetate in DCM) to give the titled compound (6.5 g, 90%yield). MS (ESI) m/z: Calc. 440.1 (M⁺). Found: 442.1 (M⁺+2).

Step 3: Preparation of4-(azetidin-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine

To tert-butyl3-(5-bromo-2-(cis-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate(6.5 g, 14 mmol) in DCM (25 mL) was added TFA (4 mL). The mixture wasstirred at room temperature for 4 h, diluted with DCM, washed with 1NNaOH solution, water, dried over sodium sulfate, filtered andconcentrated to dryness. MS (ESI) m/z Calc. 340.1 (M⁺). Found: 342.1(M⁺+2).

Step 4: Preparation of5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine

To a solution of4-(azetidin-3-yloxy)-5-bromo-N-(cis-4-methylcyclohexyl)-pyrimidin-2-amine(1.24 g, 3.64 mmol) and Et₃N (0.6 mL, 3.64 mmol) in DCM (20 mL) at 0° C.was added methanesulfonyl chloride (417 mg, 3.64 mmol). The mixture wasstirred at 0° C. for 5 h, diluted by DCM, washed with saturated aqueoussodium carbonate solution and water, dried over sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, eluted by 1% methanol in DCM) to give thetitle compound as a white solid (1.3 g, 85% yield). MS (ESI) m/z: Calc.418.1 (M⁺). Found: 420.1 (M⁺+2).

Step 5: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a solution of (R)-tetrahydrofuran-3-ol (3 g, 34.1 mmole) and Et₃N(6.9 g, 68.2 mmole) in DCM (40 mL) at 0° C. was added4-methylbenzene-1-sulfonyl chloride (7.2 g, 37.5 mmole. The mixture wasstirred at room temperature for 8 h. The mixture was washed with water,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 15% ethyl acetate in hexane) togive the title compound (6.8 g, 83% yield). MS (ESI) m/z: Calc. 242.1(M⁺). Found: 243.1 (M⁺+1).

Step 6: Preparation of(R)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (6.3g, 28.5 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.8g, 28 mmol) and K₂CO₃ (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85°C. for 15 h. The reaction mixture was diluted with ethyl acetate, washedwith water, dried over MgSO₄, filtered, and concentrated under vacuum.The residue was purified by flash chromatography (silica gel, elute: 5%ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield).MS (ESI) m/z: Calc. 290.1 (M⁺). Found: 291.1 (M⁺+1).

Step 7: Preparation ofN-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 3,5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-aminewas reacted with(R)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolaneto provide the title compound (18 mg, 45% yield). ¹H NMR (CDCl₃, 400MHz) 8.12 (s, 1H), 7.38 (m, 2H), 6.91 (m, 2H), 5.34 (m, 1H), 5.20 (sb,1H), 4.95 (m, 1H), 4.31 (m, 2H), 4.09-3.92 (m, 6H), 2.90 (s, 3H), 2.22(m, 2H), 1.80-1.57 (m, 6H), 1.23 (m, 2H), 0.94 (d, 3H). MS (ESI) m/z:Calc. 502.2 (M⁺). Found: 503.1 (M⁺+1).

Example 18 Preparation ofN-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Step 1: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a solution of (R)-tetrahydrofuran-3-ol (3 g, 34.1 mmole) and Et₃N(6.9 g, 68.2 mmole) in DCM (40 mL) at 0° C. was added4-methylbenzene-1-sulfonyl chloride (7.2 g, 37.5 mmole). The mixture wasstirred at room temperature for 8 h. The mixture was washed with water,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 15% ethyl acetate in hexane) togive the title compound (6.6 g, 80% yield). MS (ESI) m/z: Calc. 242.1(M⁺). Found: 243.1 (M⁺+1).

Step 2: Preparation of(S)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g,22.8 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.6 g,22.8 mmol) and K₂CO₃ (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85°C. for 15 h. The reaction mixture was diluted with ethyl acetate, washedwith water, dried over MgSO₄, filtered, and concentrated under vacuumThe residue was purified by flash chromatography (silica gel, elute: 5%ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield).MS (ESI) m/z: Calc. 290.2 (M⁺). Found: 291.1 (M⁺1).

Step 3: Preparation ofN-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Using the procedure of Example 1 Step 3,5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-aminewas reacted with(S)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolaneto provide the title compound (105 mg, 46% yield). ¹H NMR (CDCl₃, 400MHz) 8.12 (s, 1H), 7.38 (m, 2H), 6.91 (m, 2H), 5.34 (m, 1H), 5.20 (sb,1H), 4.95 (m, 1H), 4.31 (m, 2H), 4.09-3.92 (m, 6H), 2.90 (s, 3H), 2.22(m, 2H), 1.80-1.57 (m, 6H), 1.23 (m, 2H), 0.94 (d, 3H). MS (ESI) m/z:Calc. 502.2 (M⁺). Found: 503.1 (M⁺+1).

Examples 19-248

Compounds listed in Table 2 below were prepared using proceduresanalogous to those described above in Examples 1-18 using appropriatestarting materials which are available commercially, prepared based onprocedures known in the art, or prepared in a manner analogous to routesdescribed above for other intermediates.

TABLE 2 Ex- MS MS ample Calc: Found No. Compound Name M⁺ M⁺ +1 195-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(3- 461.2 462.3methoxybenzyloxy)-N-((1s,4s)-4- methylcyclohexyl)pyrimidin-2-amine 205-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(2,6- 425.2 426.5dimethylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 21N-((1s,4s)-4-methylcyclohexyl)-4-(oxetan-3-yloxy)- 422.3 423.45-(4-(piperidin-1-yl)phenyl)pyrimidin-2-amine 225-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin- 410.2 411.37-yl)-N-((1s,4s)-4-methylcyclohexyl)-4-(oxetan-3-yloxy)pyrimidin-2-amine 231-(3-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 452.2 453.32-((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)pyrrolidin-1-yl)ethanone 24 isopropyl3-(5-(2,3-dihydrobenzo[b][1,4]dioxin- 496.3 497.26-yl)-2-((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)pyrrolidine-1-carboxylate 25N-((1s,4s)-4-methylcyclohexyl)-4-(oxetan-3- 472.2 473.2yloxy)-5-(4-(pyrrolidin-1-ylsulfonyl)phenyl) pyrimidin-2-amine 265-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 425.2 426.2((1s,4s)-4-methylcyclohexyl)-4-(((R)-tetrahydro-furan-3-yl)methoxy)pyrimidin-2-amine 27N-((1s,4s)-4-methylcyclohexyl)-5-(4- 452.3 453.2morpholinophenyl)-4-(((R)-tetrahydro-furan-3-yl)methoxy)pyrimidin-2-amine 285-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,6- 385.2 386.2dimethoxy-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 295-(2-methyl-2H-indazol-5-yl)-N-((1s,4S)-4- 421.3 422.2methylcyclohexyl)-4-(((R)-tetrahydrofuran-3-yl)methoxy)pyrimidin-2-amine 305-(1-methyl-1H-indazol-5-yl)-N-((1s,4S)-4- 421.3 422.2methylcyclohexyl)-4-(((R)-tetrahydrofuran-3-yl)methoxy)pyrimidin-2-amine 313-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 481.3 482.22-((1s,4s)-4-methylcyclohexylamino) pyrimidin-4-yloxy)-N,N-dimethylpyrrolidine-1-carboxamide 32 N-((1s,4s)-4-methylcyclohexyl)-5-394.2 395.3 (1-methylindolin-5-yl)-4-(oxetan-3-yloxy) pyrimidin-2-amine33 N-((1s,4s)-4-methylcyclohexyl)-4-((3- 452.3 453.3methyloxetan-3-yl)methoxy)-5-(4- morpholinophenyl)pyrimidin-2-amine 345-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 425.2 426.2N-((1s,4s)-4-methylcyclohexyl)- 4-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine 35 N-((1s,4s)-4-methylcyclohexyl)-5-(1-422.3 423.3 methylindolin-5-yl)-4-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine 36 (S)-methyl3-(2-((1s,4R)-4-methylcyclo- 495.3 496.3hexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)pyrrolidine-1-carboxylate 37 methyl4-(5-(2-methyl-2H-indazol-5-yl)- 478.3 479.22-((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate 38 5-(4-(3,5-dimethyl-1H-pyrazol-1-yl)447.3 448.2 phenyl)-N-((1s,4S)-4-methylcyclo-hexyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 395-(2,3-dihydrobenzofuran-5-yl)-N-((1s,4S)-4- 395.2 396.2methylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 40N-((1s,4S)-4-methylcyclohexyl)-4-((R)- 439.3 440.3tetrahydrofuran-3-yloxy)-5-(4-(tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 414-(1,3-dioxan-5-yloxy)-5-(2,3-dihydrobenzo[b][1,4] 427.2 428.2dioxin-6-yl)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 424-(1,3-dioxan-5-yloxy)-N-((1s,4s)-4-methylcyclo- 454.3 455.1hexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine 434-methyl-N-((1s,4s)-4-methylcyclohexyl)-5-(4- 452.3 453.3morpholinophenyl)-6-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 44methyl 3-(5-(2,3-dihydrobenzo[b][1,4]dioxin- 454.2 455.36-yl)-2-((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate 454-((1,3-dioxolan-4-yl)methoxy)-5-(2,3- 427.2 428.2dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1s,4s)-4-methylcyclohexyl)pyrimidin-2-amine 464-(2-methoxyethoxy)-N-((1s,4s)-4-methylcyclo- 426.3 427.5hexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine 474-(1-(cyclopropylsulfonyl)pyrrolidin-3- 514.2 515.2yloxy)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 48 (R)-methyl3-(5-(1-methyl-1H-indazol-5-yl)-2-((1s, 464.3 465.24S)-4-methylcyclohexylamino)pyrimidin-4-yloxy) pyrrolidine-1-carboxylate49 5-(biphenyl-4-yl)-N-((1s,4s)-4-methylcyclohexyl)-4- 415.2 416.3(oxetan-3-yloxy)pyrimidin-2-amine 505-(6-(cyclohexyl(methyl)amino)pyridin-3- 451.3 452.2yl)-N-((1s,4s)-4-methylcyclo- hexyl)-4-(oxetan-3-yloxy)pyrimidin-2-amine51 N-((1s,4s)-4-methylcyclohexyl)-5-(4-(4- 437.3 438.2methylpiperazin-1-yl)phenyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 525-(4-isopropoxyphenyl)-N-((1s,4s)-4-methylcyclo- 397.2 398.3hexyl)-4-(oxetan-3-yloxy)pyrimidin-2-amine 53 (R)-methyl3-(5-(4-isopropoxyphenyl)-2-((1s,4S)-4- 468.3 469.2methylcyclohexylamino)pyrimidin-4-yloxy) pyrrolidine-1-carboxylate 54(S)-methyl 3-(2-((1s,4R)-4-methylcyclohexyl- 465.3 466.2amino)-5-(1-methylindolin-5-yl)pyrimidin-4-yloxy)pyrrolidine-1-carboxylate 55N-((1s,4S)-4-methylcyclohexyl)-5-(6-morpholino- 439.3 440.3pyridin-3-yl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 56N-((1s,4s)-4-methylcyclohexyl)-5-(6-morpholino- 425.2 426.3pyridin-3-yl)-4-(oxetan-3-yloxy)pyrimidin-2-amine 575-(2-(methoxymethyl)benzo[d]oxazol- 424.2 425.25-yl)-N-((1s,4s)-4-methylcyclo-hexyl)-4-(oxetan-3-yloxy)pyrimidin-2-amine 58N-((1s,4S)-4-methylcyclohexyl)-4-((R)-1- 515.3 516.3(methylsulfonyl)pyrrolidin-3-yloxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 59N-((1s,4s)-4-methylcyclohexyl)-4-(1- 501.2 502.3(methylsulfonyl)azetidin-3-yloxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 60 methyl3-(2-((1s,4s)-4-methylcyclohexyl- 481.3 482.3amino)-5-(4-morpholinophenyl)pyrimidin- 4-yloxy)azetidine-1-carboxylate61 N-((1s,4s)-4-methylcyclohexyl)-5-(4-(2- 452.3 453.2morpholinoethyl)phenyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 625-(2-cyclopropylbenzo[d]oxazol-5-yl)-N- 434.2 435.2((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 635-(2-cyclopropylbenzo[d]oxazol-5-yl)-N- 420.2 421.2((1s,4s)-4-methylcyclohexyl)-4-(oxetan- 3-yloxy)pyrimidin-2-amine 645-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 441.2 441.6((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro-2H-thiopyran-4-yloxy)pyrimidin-2-amine 655-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 457.2 458.3((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro-2H-thiopyran-1-oxide-4-yloxy)pyrimidin-2-amine 665-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 473.2 474,2 ((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro- 2H-thiopyran-1,1-dioxide-4-yloxy)pyrimidin-2-amine 67 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 424.3425.3 ((1s,4s)-4- methylcyclohexyl)-4-((R)-1-methylpyrrolidin-3-yloxy)pyrimidin-2-amine 685-(4-((2R,6S)-2,6-dimethylmorpholino) 466.3 467.3phenyl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 69 tert-butyl4-(4-(2-((1s,4S)-4-methylcyclohexyl- 537.3 538.1amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenyl)piperazine-1-carboxylate 701-(3-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)- 438.2 439.2 2-((1s,4s)-4-methylcyclohexylamino) pyrimidin-4-yloxy)azetidin-1-yl)ethanone 715-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N- 474.2 475.2(1s,4s)-4-methylcyclohexyl)-4-(1- (methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine 72 methyl 4-(2-((1s,4s)-4-methylcyclohexyl- 509.3510.2 amino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate 73 (R)-N,N-dimethyl-3-(2-((1s,4S)-4-508.3 509.3 methylcyclohexylamino)-5-(4-morpholino-phenyl)pyrimidin-4-yloxy)pyrrolidine-1- carboxamide 741-(methoxymethyl)-5-(2-((1s,4S)-4- 452.2 453.3methylcyclohexylamino)-4-((R)-tetrahydro-furan-3-yloxy)pyrimidin-5-yl)indolin-2-one 75N-((1s,4s)-4-methylcyclohexyl)-5-(4- 438.3 439.2(morpholinomethyl)phenyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 415.2415.5 76 5-(3-fluoro-4-isopropoxyphenyl)-N-((1s,4s)-4-methylcyclohexyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 77 (R)-methyl3-((2-((1s,4S)-4-methylcyclo- 509.3 510.3hexylamino)-5-(4-morpholinophenyl) pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate 78 N-((1s,4S)-4-methylcyclohexyl)-4-(((R)-1-529.3 530.3 (methylsulfonyl)pyrrolidin-3-yl)methoxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 79 methyl3-((2-((1s,4s)-4-methylcyclohexyl- 495.3 496.3amino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate 80N-((1s,4s)-4-methylcyclohexyl)-4-((1- 515.3 516.3(methylsulfonyl)azetidin-3-yl)methoxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 81 methyl4-((2-((1s,4s)-4-methylcyclohexyl- 523.3 524.3amino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate 82N-((1s,4s)-4-methylcyclohexyl)-4-((1- 543.3 544.3(methylsulfonyl)piperidin-4-yl)methoxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 834-(4-methoxyphenyl)-N-((1s,4s)-4-methylcyclo- 458.3 459.4hexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine 84N-((1s,4s)-4-methylcyclohexyl)-4-(1- 502.2 503.1(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 85(R)-N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexyl- 509.3 510.3amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)pyrrolidine-1-carboxamide 86 methyl4-(2-((1s,4s)-4-methylcyclohexyl- 510.3 511.1amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate 873-chloro-2-(2-((1s,4s)-4-methylcyclohexyl- 460.2 461.2amino)-5-(4-morpholinophenyl) pyrimidin-4-yloxy)propan-1-ol 884-(2-((1s,4s)-4-methylcyclohexylamino)-4-((R)- 369.2 371.2tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenol 89 tert-butyl3-(2-((1s,4s)-4-methylcyclohexyl- 523.3 524.4amino)-5-(4-morpholinophenyl)pyrimidin-4- yloxy)azetidine-1-carboxylate90 N-((1s,4S)-4-methylcyclohexyl)-5-(4-((tetrahydro- 453.3 454.2furan-3-yl)methoxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 914-(2-((1s,4s)-4-methylcyclohexylamino)-4- 383.2 384.2(tetrahydro-2H-pyran-4-yloxy) pyrimidin-5-yl)phenol 92N-((1s,4S)-4-methylcyclohexyl)-5-(4- 502.2 503.3(morpholinosulfonyl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 93N-((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro- 453.3 454.32H-pyran-4-yloxy)-5-(4-((R)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-2-amine 94 tert-butyl4-(4-(2-((1s,4S)-4-methylcyclohexyl- 537.3 538.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenyl)piperazine-1-carboxylate 95(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 466.3 467.1tetrahydrofuran-3-yloxy)pyrimidin-5- yl)phenyl)(morpholino)methanone 965-(1-isopropylindolin-5-yl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3- 436.3 437.4yloxy)pyrimidin-2-amine 97N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholino- 500.3 501.3phenyl)-4-(tetrahydro-2H-thiopyran-1,1-dioxide-4-yloxy-)pyrimidin-2-amine 98N-((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro- 453.3 454.22H-pyran-4-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 99 tert-butyl3-(5-(4-hydroxyphenyl)-2-((1s,4s)-4- 454.3 455.3methylcyclohexylamino)pyrimidin-4-yloxy) azetidine-1-carboxylate 100N-((1s,4S)-4-methylcyclohexyl)-5-(4-(piperazin-1- 437.3 438.3yl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 468.3 469.4101 tert-butyl 4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl) phenylcarbamate 102(S)-tert-butyl 3-(4-(2-((1s,4S)-4-methylcyclohexyl- 538.3 539.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxylate 103 methyl3-(4-(2-((1s,4S)-4-methylcyclohexylamino)- 496.3 497.44-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxylate 104N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexyl- 530.3 531.4amino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy) azetidine-1-sulfonamide105 5-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-N-((1s, 423.3 424.34S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 1064-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 452.2 453.4tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenyl) morpholin-3-one 107tert-butyl 3-(4-(2-((1s,4S)-4-methylcyclohexyl- 538.3 539.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxylate 1085-(3-methylbenzo[d]isoxazol-5-yl)-N-(1s,4S)-4- 408.2 409.3methylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 109tert-butyl 3-(4-(2-((1s,4S)-4-methylcyclohexyl- 524.3 525.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)azetidine-1-carboxylate 110N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholino- 468.3 469.3phenyl)-4-(tetrahydro-2H-thiopyran-4-yloxy) pyrimidin-2-amine 111(R)-N-isopropyl-5-(4-morpholinophenyl)-4- 384.2 385.3(tetrahydrofuran-3-yloxy)pyrimidin-2-amine 112N,N-dimethyl-3-(4-(2-((1s,4S)-4-methylcyclohexyl- 509.3 510.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1-carboxamide 113N-((1s,4S)-4-methylcyclohexyl)-5-(4-(oxetan-3- 425.2 426.2yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 114N-((1s,4S)-4-methylcyclohexyl)-5-(4-(tetrahydro- 469.2 470.22H-thiopyran-4-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 115N-((1s,4S)-4-methylcyclohexyl)-5-(4- 452.3 453.3(morpholinomethyl)phenyl)-4-((R)-tetrahydro-furan-3-yloxy)pyrimidin-2-amine 116 tert-butyl4-(5-(4-hydroxyphenyl)-2-((1s,4s)-4- 482.3 483.4methylcyclohexylamino)pyrimidin-4-yloxy) piperidine-1-carboxylate 117N-((1s,4S)-4-methylcyclohexyl)-5-(4-(4- 515.3 516.4(methylsulfonyl)piperazin-1-yl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 118 methyl4-(4-(2-((1s,4S)-4-methylcyclohexyl- 495.3 496.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenyl)piperazine-1-carboxylate 1194-(2-((1s,4s)-4-methylcyclohexylamino)-4- 355.2 356.1(oxetan-3-yloxy)pyrimidin-5-yl)phenol 120N-((1s,4S)-4-methylcyclohexyl)-5-(4-(1- 516.2 517.2(methylsulfonyl)pyrrolidin-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 1211-(3-(4-(2-((1s,4S)-4-methylcyclohexyl- 481.2 480.3amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidin-1-yl)ethanone 122cyclopropyl(3-(2-((1s,4s)-4-methylcyclohexyl- 491.3 492.4amino)-5-(4-morpholinophenyl)pyrimidin- 4-yloxy)azetidin-1-yl)methanone123 tert-butyl 3-(5-(4-(2-methoxyethoxy)phenyl)-2-((1s, 512.3 513.44s)-4-methylcyclohexylamino)pyrimidin-4- yloxy)azetidine-1-carboxylate124 tert-butyl 4-(2-((1s,4s)-4-methylcyclohexyl- 552.3 553.3amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate 1254-(1-(cyclopropylsulfonyl)azetidin-3-yloxy)-N-((1s, 527.3 528.34s)-4-methylcyclohexyl)-5-(4-morpholinophenyl) pyrimidin-2-amine 126(R)-N-isopropyl-4-(tetrahydrofuran-3-yloxy)-5-(4- 383.2 384.3(trifluoromethoxy)phenyl)pyrimidin-2-amine 127N-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 438.3 439.5tetrahydrofuran-3-yloxy)pyrimidin-5- yl)phenyl)isobutyramide 128N-((1s,4S)-4-methylcyclohexyl)-5-(4-(pyrrolidin-3- 438.3 439.4yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 1295-(4-((isopropylamino)methyl)phenyl)-N-((1s,4S)-4- 424.3 425.2methylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 1305-(4-((benzylamino)methyl)phenyl)-N-((1s,4S)-4- 472.3 473.5methylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 131N-((1s,4S)-4-methylcyclohexyl)-5-(4-(piperidin-1- 450.3 451.4ylmethyl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 1321-(4-(4-(2-((1s,4S)-4-methylcyclohexyl- 479.3 480.4amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenyl)piperazin-1-yl)ethanone 1332-methoxy-1-(3-(2-((1s,4s)-4-methylcyclohexyl- 495.3 496.4amino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy) azetidin-1-yl)ethanone134 4-(1-(ethylsulfonyl)azetidin-3-yloxy)-N-((1s,4s)-4- 515.3 516.4methylcyclohexyl)-5-(4-morpholinophenyl) pyrimidin-2-amine 135N-((1s,4S)-4-methylcyclohexyl)-5-(4-(piperazin-1- 451.3 452.2ylmethyl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 136N,N-dimethyl-3-(4-(2-((1s,4S)-4-methylcyclohexyl- 495.3 496.1amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)azetidine-1-carboxamide 137N-((1s,4S)-4-methylcyclohexyl)-5-(4-(tetra- 453.3 453.9hydro-2H-pyran-3-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 138 methyl3-(4-(2-((1s,4S)-4-methylcyclohexyl- 482.3 483.1amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)azetidine-1-carboxylate 1391-(3-(4-(2-((1s,4S)-4-methylcyclohexyl- 466.3 467.1amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)azetidin-1-yl)ethanone 140(3-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 536.3 537.0morpholinophenyl)pyrimidin-4-yloxy)azetidin-1- yl)(morpholino)methanone141 N-((1s,4S)-4-methylcyclohexyl)-5-(4- 458.3 459.1((phenylamino)methyl)phenyl)-4-((R)-tetrahydro-furan-3-yloxy)pyrimidin-2-amine 1425-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- 441.3 442.1methylcyclohexyl)-4-(tetrahydro-2H-pyran-4- yloxy)pyrimidin-2-amine 1435-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- 489.2 490.4methylcyclohexyl)-4-(tetrahydro-2H-thiopyran-1,1-dioxide-4-yloxy)pyrimidin-2-amine 1444-(4-methoxyphenyl)-5-(2-methyl-2H-indazol- 427.2 427.85-yl)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 145N-(2,6-dimethylcyclohexyl)-5-(4-morpholino- 452.3 452.9phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 146(R)-N-methyl-5-(4-morpholinophenyl)-N-phenyl-4- 432.2 432.8(tetrahydrofuran-3-yloxy)pyrimidin-2-amine 147N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydro- 437.2 437.8furan-3-yloxy)-5-(4-(trifluoromethoxy)phenyl) pyrimidin-2-amine 148methyl 4-(4-(2-((1s,4S)-4-methylcyclohexyl- 509.3 509.8amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)piperazine-1-carboxylate 149N-((1s,4S)-4-methylcyclohexyl)-5-(4-((4- 529.3 529.8(methylsulfonyl)piperazin-1-yl)methyl) phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 150 1-(4-(4-(2-((1s,4S)-4-methylcyclohexyl-493.3 493.9 amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)piperazin-1-yl) ethanone 151 tert-butyl4-(4-(2-((1s,4S)-4-methylcyclohexyl- 551.4 552.2amino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)piperazine-1-carboxylate 152N-((1s,4s)-4-methylcyclohexyl)-4-(1- 530.3 530.8(methylsulfonyl)piperidin-4-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 1535-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- 490.2 490.8methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine 154N-((1s,4S)-4-methylcyclohexyl)-5-(4-(pyrrolidin-1- 422.3 422.9yl)phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 155N-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 474.2 475.2tetrahydrofuran-3-yloxy)pyrimidin-5- yl)phenylsulfonyl)acetamide 156methyl 4-(5-(4-(2-methoxyethoxy)phenyl)-2-((1s, 498.3 499.44s)-4-methylcyclohexylamino)pyrimidin-4-yloxy) piperidine-1-carboxylate157 N-(2,4-dimethoxybenzyl)-N-(4-(2-((1s,4S)-4- 574.3 575.4methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)acetamide 1585-(4-((2,4-dimethoxybenzylamino)methyl) 532.3 532.8phenyl)-N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 159N-((1s,4S)-4-methylcyclohexyl)-5-(3- 467.3 468.3((tetrahydro-2H-pyran-4-yl)methoxy) phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 160N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydro- 439.3 440.3furan-3-yloxy)-5-(3-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 161N-((1s,4s)-4-methylcyclohexyl)-4-(methylthio)-5- 398.2 398.8(4-morpholinophenyl)pyrimidin-2-amine 162 tert-butyl4-(5-(4-(2-methoxyethoxy)phenyl)-2-((1s, 540.3 541.44s)-4-methylcyclohexylamino)pyrimidin-4-yloxy) piperidine-1-carboxylate163 5-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- 476.3 443.1methylcyclohexyl)-4-(piperidin-4-yloxy) (—HCl) pyrimidin-2-aminehydrochloride 164 4-(2-(2,6-dimethylcyclohexylamino)-4-((R)- 383.2 384.2tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenol 165N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydro- 439.3 440.2furan-3-yloxy)-5-(3-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 166 5-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4-413.2 414.2 methylcyclohexyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 1675-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- 457.2 458.2methylcyclohexyl)-4-(tetrahydro-2H-thiopyran-4- yloxy)pyrimidin-2-amine168 N-((1s,4s)-4-methylcyclohexyl)-4-(oxetan-3-yloxy)- 425.2 426.25-(4-((S)-tetrahydrofuran-3-yloxy)phenyl) pyrimidin-2-amine 169tert-butyl methyl(4-(2-((1s,4S)-4-methylcyclohexyl- 482.3 483.2amino)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-5-yl)phenyl)carbamate170 N-(2,6-dimethylcyclohexyl)-4-((R)- 453.3 454.4tetrahydrofuran-3-yloxy)-5-(4-((S)- tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 171 4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)-396.2 397.1 tetrahydrofuran-3-yloxy) pyrimidin-5-yl)benzamide 1725-(biphenyl-4-yl)-N-((1s,4S)-4-methylcyclo- 429.2 430.2hexyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 173N-((1s,4S)-4-methylcyclohexyl)-5-(4-phenoxy- 445.2 446.2phenyl)-4-((R)-tetrahydrofuran-3-yloxy) pyrimidin-2-amine 1744-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 432.2 433.1tetrahydrofuran-3-yloxy)pyrimidin-5- yl)benzenesulfonamide 175 isopropyl4-(2-((1s,4s)-4-methylcyclohexyl- 538.3 539.3amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate 176 ethyl2-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 454.3 455.5morpholinophenyl)pyrimidin-4-yloxy)acetate 177N-((1s,4s)-4-methylcyclohexyl)-4-(piperidin- 488.3 453.34-yloxy)-5-(4-((S)-tetrahydrofuran-3- (—HCl)yloxy)phenyl)pyrimidin-2-amine hydrochloride 1785-(4-(2-methoxyethyl)phenyl)-N-((1s,4s)-4- 397.2 398.1methylcyclohexyl)-4-(oxetan-3-yloxy) pyrimidin-2-amine 1794-(isopropylthio)-N-((1s,4s)-4-methylcyclo- 426.3 427.2hexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine 1804-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 378.2 379.2tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzonitrile 181N-((1s,4S)-4-methylcyclohexyl)-5-(4-(tetrahydro- 501.2 501.82H-thiopyran-1,1-dioxide-4-yloxy)phenyl)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-2-amine 182 methyl3-(5-(4-(2-methoxyethyl)phenyl)-2-((1s, 454.3 455.44s)-4-methylcyclohexylamino)pyrimidin-4- yloxy)azetidine-1-carboxylate183 5-(4-(1H-tetrazol-5-yl)phenyl)-N-((1s,4S)-4- 421.2 422.3methylcyclohexyl)-4-((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 184tert-butyl 3-(5-(4-(2-methoxyethyl) 496.3 497.3phenyl)-2-((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate 185N-((1s,4S)-4-methylcyclohexyl)-4-((R)-tetrahydro- 439.3 440.3furan-3-yloxy)-5-(3-(tetrahydrofuran-3-yloxy) phenyl)pyrimidin-2-amine186 N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholino- 484.3 485.2phenyl)-4-(tetrahydro-2H-thiopyran-1-oxide-4- yloxy-)pyrimidin-2-amine187 3-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 397.2 398.2tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzoic acid 1884-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 474.2 475.3tetrahydrofuran-3-yloxy)pyrimidin-5-yl)-N- (methylsulfonyl)benzamide 189N-(N,N-dimethylsulfamoyl)-4-(2-((1s,4S)-4- 503.2 504.3methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzamide 190N-cyano-4-(2-((1s,4S)-4-methylcyclohexylamino)-4- 421.2 422.3((R)-tetrahydrofuran-3-yloxy)pyrimidin- 5-yl)benzamide 191 methyl3-(5-(4-(2-methoxyethoxy)phenyl)-2- 470.3 471.1((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)azetidine-1-carboxylate 192N-(2,4-dimethoxybenzyl)-N-(4-(2-((1s,4S)-4- 636.3 637.1methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)benzamide 193 tert-butyl3-(2-((1s,4s)-4-methylcyclohexyl- 587.3 588.2amino)-5-(4-(morpholinosulfonyl)phenyl)pyrimidin-4-yloxy)azetidine-1-carboxylate 194N-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 424.3 425.3tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl) acetamide 195N-(4-(2-((1s,4S)-4-methylcyclohexylamino)-4-((R)- 486.3 487.2tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl) benzamide 1962-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 426.2 427.1morpholinophenyl)pyrimidin-4-yloxy)acetic acid 1975-(4-(2-methoxyethyl)phenyl)-N-((1s,4s)-4- 425.3 426.2methylcyclohexyl)-4-(tetrahydro-2H-pyran-4- yloxy)pyrimidin-2-amine 1985-(4-(2-methoxyethyl)phenyl)-N-((1S,4S)-4- 473.2 474.1methylcyclohexyl)-4-(tetrahydro-2H-thiopyran-1,1-dioxide-4-yloxy)pyrimidin-2-amine 199 tert-butyl4-(5-(4-(2-methoxyethyl)phenyl)-2-((1s, 524.3 525.34s)-4-methylcyclohexylamino)pyrimidin-4-yloxy) piperidine-1-carboxylate200 5-(4-(2-methoxyethoxy)phenyl)-4-(1-methylaze- 426.3 427.2tidin-3-yloxy)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 2015-(4-(2-methoxyethyl)phenyl)-4-(1-methylaze- 410.3 411.2tidin-3-yloxy)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 202tert-butyl 3-((5-(4-hydroxyphenyl)-2-((1s,4s)-4- 468.3 469.2methylcyclohexylamino)pyrimidin-4- yloxy)methyl)azetidine-1-carboxylate203 (R)-tert-butyl 3-((5-(4-hydroxyphenyl)-2((1s,4S)-4- 482.3 483.2methylcyclohexylamino)pyrimidin-4-yloxy)methyl)pyrrolidine-1-carboxylate 204 tert-butyl4-((5-(4-hydroxyphenyl)-2-((1s,4s)-4- 496.3 497.2methylcyclohexylamino)pyrimidin-4- yloxy)methyl)piperidine-1-carboxylate205 2-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 503.2 504.2morpholinophenyl)pyrimidin-4-yloxy)-N- (methylsulfonyl)acetamide 206methyl 4-(5-(4-(2-methoxyethyl)phenyl)-2-((1s, 482.3 483.44s)-4-methylcyclohexylamino)pyrimidin-4- yloxy)piperidine-1-carboxylate207 N,N-dimethyl-3-(2-((1s,4s)-4- 531.3 532.4methylcyclohexylamino)-5-(4-((R)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy) azetidine-1-sulfonamide 208tert-butyl 4-((2-((1s,4s)-4-methylcyclohexyl- 566.4 567.3amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl)piperidine-1-carboxylate 209 tert-butyl4-((2-((1s,4s)-4-methylcyclohexyl- 566.4 567.3amino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) piperidine-1-carboxylate 210(R)-tert-butyl 3-((2-((1s,4S)-4- 552.3 553.3methylcyclohexylamino)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy) methyl)pyrrolidine-1-carboxylate211 (R)-tert-butyl 3-((2-((1s,4S)-4- 552.3 553.3methylcyclohexylamino)-5-(4-((R)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy) methyl)pyrrolidine-1-carboxylate212 (R)-tert-butyl 3-(4-(2-((1s,4S)-4- 538.3 539.3methylcyclohexylamino)-4-((R)-tetrahydro-furan-3-yloxy)pyrimidin-5-yl)phenoxy) pyrrolidine-1-carboxylate 213tert-butyl 3-(2-((1s,4s)-4-methylcyclohexyl- 524.3 525.5amino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-carboxylate 214N,N-dimethyl-3-(2-((1s,4s)-4- 531.3 532.5methylcyclohexylamino)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy) azetidine-1-sulfonamide 2154-(1-(cyclopropylsulfonyl)azetidin-3-yloxy)-N- 528.2 529.4((1s,4s)-4-methylcyclohexyl)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 216N,N-dimethyl-3-(2-((1s,4s)-4- 594.2 595.4 methylcyclohexylamino)-5-(4-(morpholinosulfonyl)phenyl)pyrimidin-4- yloxy)azetidine-1-sulfonamide217 N,N-dimethyl-3-(2-((1s,4s)-4- 412.3 413.4methylcyclohexylamino)-5-(4- (morpholinosulfonyl)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide 2184-(4-methoxyphenyl)-5-(2-methyl-2H-indazol- 427.2 428.46-yl)-N-((1s,4s)-4-methylcyclohexyl) pyrimidin-2-amine 219N-((1s,4S)-4-methylcyclohexyl)-4-((R)-pyrro- 452.3 453.2lidin-3-ylmethoxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 220 tert-butyl3-(2-((1s,4s)-4-methylcyclohexyl- 524.3 525.5amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-carboxylate 221N-((1s,4s)-4-methylcyclohexyl)-4-((1- 516.2 517.3(methylsulfonyl)azetidin-3-yl)methoxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 222N,N-dimethyl-4-((2-((1s,4s)-4- 573.3 574.5methylcyclohexylamino)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) piperidine-1-sulfonamide223 2-methyl-6-(2-((1s,4S)-4-methylcyclohexyl- 422.2 423.2amino)-4-((R)-tetrahydrofuran-3-yloxy) ypyrimidin-5-yl)isoindolin-1-one224 N,N-dimethyl-3-42-((1s,4s)-4- 545.3 546.4methylcyclohexylamino)-5-(4-((R)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) azetidine-1-sulfonamide225 N-((1s,4s)-4-methylcyclohexyl)-4-((1- 516.2 517.3(methylsulfonyl)azetidin-3-yl)methoxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 226N,N-dimethyl-3-((2-((1s,4s)-4- 545.3 546.7methylcyclohexylamino)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) azetidine-1-sulfonamide227 5-(2-(methoxymethyl)-1-methyl-1H-benzo[d] 437.2 48.4imidazol-5-yl)-N-((1s,4s)-4-methylcyclo-hexyl)-4-(oxetan-3-yloxy)pyrimidin-2-amine 228N-((1s,4s)-4-methylcyclohexyl)-4-(piperidin-4- 466.3 467.4ylmethoxy)-5-(4-((R)-tetrahydrofuran-3- yloxy)phenyl)pyrimidin-2-amine229 N-((1s,4s)-4-methylcyclohexyl)-4-(1- 565.2 566.2(methylsulfonyl)azetidin-3-yloxy)-5-(4-(morpholinosulfonyl)phenyl)pyrimidin-2-amine 230N-((1s,4S)-4-methylcyclohexyl)-4-(((R)-1- 530.3 531.4(methylsulfonyl)pyrrolidin-3-yl)methoxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 2312-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 442.3 443.4morpholinophenyl)pyrimidin-4-yloxy) propane-1,3-diol 2322-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4- 425.2 426.2morpholinophenyl)pyrimidin-4-yloxy)acetamide 233N-((1s,4s)-4-methylcyclohexyl)-4-(1- 579.2 580.2(methylsulfonyl)azetidin-3-yloxy)-5-(4-((R)-1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl) pyrimidin-2-amine 234N-((1s,4s)-4-methylcyclohexyl)-4-(1- 579.2 580.2(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-1-(methylsulfonyl)pyrrolidin-3-yloxy)phenyl) pyrimidin-2-amine 235tert-butyl 3-((2-((1s,4s)-4-methylcyclohexyl- 538.3 539.5amino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate 236N,N-dimethyl-4-((2-((1s,4s)-4- 573.3 574.3methylcyclohexylamino)-5-(4-((R)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) piperidine-1-sulfonamide237 tert-butyl 3-((2-((1s,4s)-4-methylcyclohexyl- 538.3 539.3amino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl)azetidine-1-carboxylate 238N1,N1-dimethyl-N2-(4-(2-((1s,4S)-4- 453.3 454.5methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)benzyl)ethane-1,2-diamine 239(R)-N,N-dimethyl-3-((2-((1s,4S)-4- 559.3 560.4methylcyclohexylamino)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-4-yloxy)methyl) pyrrolidine-1-sulfonamide240 N,N-dimethyl-2-(2-((1s,4s)-4- 453.3 454.5methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)acetamide 241N-methyl-2-(2-((1s,4s)-4-methylcyclohexyl- 439.3 440.4amino)-5-(4-morpholinophenyl)pyrimidin- 4-yloxy)acetamide 242N-((1s,4S)-4-methylcyclohexyl)-4-(((R)-1- 530.3 531.5(methylsulfonyl)pyrrolidin-3-yl)methoxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 2434-(azetidin-3-ylmethoxy)-N-((1s,4s)-4- 438.3 439.4methylcyclohexyl)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 244 (R)-N,N-dimethyl-3-((2-((1s,4S)-4-559.3 560.4 methylcyclohexylamino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl) pyrimidin-4-yloxy)methyl)pyrrolidine-1-sulfonamide 245 N-((1s,4S)-4-methylcyclohexyl)-4-((R)-452.3 453.5 pyrrolidin-3-ylmethoxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 2464-(methoxymethyl)-N-((1s,4s)-4-methylcyclo- 468.3 469.3hexyl)-5-(4-morpholinophenyl)-6-(oxetan-3-yloxy) pyrimidin-2-amine 247N-((1s,4R)-4-methylcyclohexyl)-5-(4- 514.3 515.3morpholinophenyl)-4-phenyl-6-((S)-tetrahydro-furan-3-yloxy)pyrimidin-2-amine 248N-((1s,4R)-4-methylcyclohexyl)-4-phenyl-6-((S)- 515.3 516.3tetrahydrofuran-3-yloxy)-5-(4-((S)-tetrahydro-furan-3-yloxy)phenyl)pyrimidin-2-amine

Example 249 Preparation of4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholinophenyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine

Synthetic Overview:

Step 1: Preparation of 5-Bromo-6-(Chloromethyl)uracil (1)

To a solution of 6-(chloromethyl)uracil (2.0 g, 12.5 mmol) in DMF (15mL) at 0° C. was added NBS (recrystallized, 2.44 g, 13.7 mmol). Themixture was stirred at 0° C. for 1.5 h, and then quenched by ice water.The precipitate was collected by filtration and washed with AcOH andwater to give the title compound (2.35 g, 69%) as a white solid. ¹H NMR(DMSO, 500 MHz) δ 1.66 (s, 1H), δ 11.61 (s, 1H), δ 4.47 (s, 2H). MS(Multimode, M+H⁺) C₅H₅BrClN₂O₂, calcd. 238.9. found 238.9.

Step 2: Preparation 5-Bromo-2,4-dichloro-6-(Chloromethyl)pyrimidine (2)

To a suspension of 5-bromo-6-(chloromethyl)uracil (1) (3.47 g, 14.64mmol) in POCl₃ (30 mL) at room temperature was added one drop of DMF.The mixture was stirred and heated at 110° C. overnight. Then reactionwas cooled and concentrated in vacuo, and the residue was purified usingISCO chromatography (80 g silica gel, 0-20% EtOAc in hexanes in 40 min)to give the title compound (3.46 g, 88%) as a white solid. ¹H NMR (DMSO,500 MHz) δ 4.88 (s, 2H). MS (ESI, M+H⁺) C₅H₃BrCl₃N₂, calcd. 274.8. found274.8.

Step 3: Preparation 5-Bromo-2,4-dichloro-6-(methoxymethyl)pyrimidine (3)

To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (2)(600 mg, 2.19 mmol) in anhydrous MeOH (15 mL) at 0° C. was added NaOMe(25% wt in MeOH, 521 mg, 2.41 mmol). The mixture was stirred at 0° C.for 30 min and then allow warm to room temperature and stirredovernight. After this time the reaction mixture was concentrated invacuo. The residue was purified using ISCO chromatography (24 g silicagel, 0-1.5% EtOAc in hexanes in 40 min) to give the title compound (480mg, 81%) as a white solid. ¹H NMR (DMSO, 300 MHz) δ 4.77 (s, 2H), 4.04(s, 3H).

Step 4: Preparation of5-Bromo-2-chloro-4-(methoxymethyl)-6-(oxetan-3-yloxy)pyrimidine (4)

To a solution of 3-hydroxyoxetane (76 mg, 1.02 mmol) in anhydrous THF (8mL) at r.t. was added NaH (60% in mineral oil, 39 mg, 0.97 mmol). Themixture was stirred at r.t. for 5 min until there was no hydrogenbubbles generated. 5-bromo-2,4-dichloro-6-(methoxymethyl)pyrimidine (3)(250 mg, 0.93 mmol) was added and the resulting reaction mixture wasstirred at r.t. overnight. The reaction was quenched with aqueous NH₄Cland extracted with EtOAc. The organic layer was separated, washed withaqueous NaHCO₃, dried (Na₂SO₄) and concentrated in vacuo. The residuewas purified using ISCO chromatography (24 g silica gel, 0-20% EtOAc inhexanes in 40 min) to give the title compound (207 mg, 73%) as a whitesolid. ¹H NMR (DMSO, 500 MHz) δ 5.57-5.52 (m, 1H), 4.91-4.86 (m, 2H),4.68 (s, 2H), 4.61-4.57 (m, 2H), 3.98 (s, 3H).

Step 5: Preparation of5-Bromo-4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(5)

To a solution of5-bromo-2-chloro-4-(methoxymethyl)-6-(oxetan-3-yloxy)pyrimidine (4) (195mg, 0.51 mmol) in EtOH (6 mL) was added cis-4-methylcyclohexylaminehydrochloride (113 mg, 0.76 mmol), followed by triethylamine (0.21 mL).The mixture was refluxed with an oil bath at 80° C. for 8 h. Aftercooling to room temperature, the reaction mixture was diluted withCH₂Cl₂ and washed with H₂O. The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by ISCOchromatography (12 g silica gel, 0-25% EtOAc in hexanes in 40 min) togive the title compound (100 mg, 41%) as a colorless gel. ¹H NMR (CDCl₃,500 MHz) δ 5.61 (m, 1H), 4.98-4.93 (m, 2H), 4.84-4.79 (m, 2H), 4.03 (s,3H), 3.91 (s, 2H), 2.73-2.64 (m 1H), 1.71-1.51 (m, 9H), 0.94 (d, 3H). MS(Multimode, M+H⁺) C₁₆H₂₄N₃O₃, calcd. 386.3. found 386.1.

Step 6: Preparation of4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-5-(4-morpholinophenyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine

To a mixture of5-bromo-4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(5) (60.0 mg, 0.16 mmol), 4-morpholinophenyl boronic acid (143.0 mg,0.31 mmol), Pd(dppf)₂Cl₂ (13.0 mg, 0.016 mmol) and Cs₂CO₃ (156 mg, 0.48mmol) was added 1,4-dioxane (1 mL), DMF (1 mL) and H₂O (1 mL). Themixture was purged with argon, and heated with an oil bath at 100° C.for 5 minutes. After cooling to room temperature, the reaction mixturewas diluted with EtOAc, and filtered. The organic layer was separated,washed with brine and 5% aqueous LiCl, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by ISCO chromatography (24 g silicagel, 0-2.5% MeOH/CH₂Cl₂ in 40 min) to give the title compound (18.0 mg,25%) as a white foam. ¹H NMR (DMSO, 500 MHz) 7.10 (d, 2H), 6.97 (d, 2H),5.58 (bd, 1H), 4.91 (t, 2H), 4.63 (t, 2H), 3.81 (s, 3H), 3.75 (t, 4H),3.44 (s, 2H), 3.15 (t, 4H), 1.79-1.69 (m, 1H), 1.44-1.14 (m, 10H), 0.83(d, 3H); MS (Multimode, M+H⁺) C₂₆H₃₇N₄O₄, calcd. 469.3. found 469.3.

Example 250 Preparation of4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Step 1: Preparation 5-Bromo-2,4-dichloro-6-(methoxymethyl)pyrimidine (1)

To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (600mg, 2.19 mmol) in anhydrous MeOH (15 mL) at 0° C. was added NaOMe (25%wt in MeOH, 521 mg, 2.41 mmol). The mixture was stirred at 0° C. for 30min and then allow warm to room temperature and stirred overnight. Afterthis time the reaction mixture was concentrated in vacuo. The residuewas purified using ISCO chromatography (24 g silica gel, 0-1.5% EtOAc inhexanes in 40 min) to give the title compound (480 mg, 81%) as a whitesolid. ¹H NMR (DMSO, 300 MHz) δ 4.77 (s, 2H), 4.04 (s, 3H).

Step 2: Preparation of5-Bromo-2-chloro-4-(methoxymethyl)-6-(oxetan-3-yloxy)pyrimidine (2)

To a solution of 3-hydroxyoxetane (76 mg, 1.02 mmol) in anhydrous THF (8mL) at r.t. was added NaH (60% in mineral oil, 39 mg, 0.97 mmol). Themixture was stirred at r.t. for 5 min until there was no hydrogenbubbles generated. 5-bromo-2,4-dichloro-6-(methoxymethyl)pyrimidine (1)(250 mg, 0.93 mmol) was added and the resulting reaction mixture wasstirred at r.t. overnight. The reaction was quenched with aqueous NH₄Cland extracted with EtOAc. The organic layer was separated, washed withaqueous NaHCO₃, and dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified using ISCO chromatography (24 g silica gel, 0-20%EtOAc in hexanes in 40 min) to give the title compound (207 mg, 73%) asa white solid. ¹H NMR (DMSO, 500 MHz) δ 5.57-5.52 (m, 1H), 4.91-4.86 (m,2H), 4.68 (s, 2H), 4.61-4.57 (m, 2H), 3.98 (s, 3H).

Step 3: Preparation of5-Bromo-4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(3)

To a solution of5-bromo-2-chloro-4-(methoxymethyl)-6-(oxetan-3-yloxy)pyrimidine (2) (195mg, 0.51 mmol) in EtOH (6 mL) was added cis-4-methylcyclohexylaminehydrochloride (113 mg, 0.76 mmol), followed by triethylamine (0.21 mL).The mixture was refluxed with an oil bath at 80° C. for 8 h. Aftercooling to room temperature, the reaction mixture was diluted withCH₂Cl₂, and washed with H₂O. The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified by ISCOchromatography (12 g silica gel, 0-25% EtOAc/hexanes in 40 min) to givethe title compound (3) (100 mg, 41%) as a colorless gel. ¹H NMR (CDCl₃,500 MHz) δ 5.61 (m, 1H), 4.98-4.93 (m, 2H), 4.84-4.79 (m, 2H), 4.03 (s,3H), 3.91 (s, 2H), 2.73-2.64 (m, 1H), 1.71-1.51 (m, 9H), 0.94 (d, 3H).MS (Multimode, M+H⁺) C₁₆H₂₅N₃O₃, calcd. 386.1. found 386.1.

Step 4: Preparation of4-(4-(methoxymethyl)-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol(4)

To a mixture of5-bromo-4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(3) (100.0 mg, 0.26 mmol), 4-hydroxyphenyl boronic acid (43.0 mg, 0.31mmol), Pd(dppf)₂Cl₂ (21.0 mg, 0.026 mmol) and Cs₂CO₃ (254 mg, 0.78 mmol)was added 1,4-dioxane (1 mL), DMF (1 mL) and H₂O (1 mL). The mixture waspurged with argon, and heated with an oil bath at 100° C. for 10 min.After cooling to room temperature, the reaction mixture was diluted withEtOAc, and filtered. The organic layer was separated, washed with brineand 5% aqueous LiCl, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by ISCO chromatography (12 g silica gel, 0-4% MeOHin CH₂Cl₂ in 40 min) to give the title compound (26.0 mg, 25%) as awhite foam. ¹H NMR (DMSO, 500 MHz) δ 9.52 (s, 1H), 7.04 (d, 2H), 6.79(d, 2H), 5.58 (bd, 1H), 4.90 (t, 2H), 4.63 (t, 2H), 3.81 (s, 3H), 3.41(s, 2H), 1.75-1.67 (m, 1H), 1.44-1.13 (m, 10H), 0.83 (d, 3H).

Step 5: Preparation of4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

To a solution of4-(4-(methoxymethyl)-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol(4) (26.0 mg, 0.065 mmol) in anhydrous DMF (1 mL) at r.t. was addedCs₂CO₃ (63.0 mg, 0.20 mmol). The mixture was stirred at r.t. for 10 minfollowed by (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (27.0 mg,0.11 mmol). The reaction mixture was stirred at r.t. overnight, and thenheated with an oil bath at 40° C. for 6 h. After this time the reactionwas quenched with H₂O and extracted with EtOAc. The organic layer wasseparated, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified using ISCO chromatography (12 g silica gel, 0-4% MeOH in CH₂Cl₂in 40 min) to give the title compound (16 mg, 52%) as a colorless gel.¹H NMR (DMSO, 500 MHz) δ 7.17 (d, 2H), 6.95 (d, 2H), 5.59 (bd, 1H),5.07-5.03 (m, 1H), 4.91 (t, 2H), 4.63 (t, 2H), 3.93-3.89 (m, 1H),3.88-3.74 (m, 6H), 3.41 (s, 2H), 2.28-2.20 (m, 1H), 2.02-1.95 (m, 1H),1.77-1.66 (m, 1H), 1.45-1.11 (m, 10H), 0.82 (d, 3H); MS (Multimode,M+H⁺) C₂₆H₃₆N₃O₅, calcd. 470.3. found 470.2.

Example 251 Preparation of4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

Step 1: Preparation of5-bromo-2-chloro-4-methyl-6-(oxetan-3-yloxy)pyrimidine (1)

To a solution of oxetan-3-ol (0.368 g, 4.96 mmol) in anhydrous THF (16mL) at 0° C. was added NaH (60% in mineral oil, 213 mg, 5.32 mmol). Themixture was stirred at 0° C. for 20 min, then5-bromo-2,4-dichloro-6-methylpyrimidine (0.800 g, 3.30 mmol) was addedto the mixture at 0° C. and stirred for 5 min. After this time thereaction was quenched with saturated aqueous NH₄Cl and extracted withEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified using ISCO chromatography (24 gsilica gel, 1-25% EtOAc in hexanes in 40 min) to give the title compound(0.566 g, 61%) as a white oil. ¹H NMR (CDCl₃, 500 MHz) δ 5.71-5.66 (m,1H), 5.030-4.99 (m, 2H), 4.79-4.76 (m, 2H), 2.59 (s, 3H).

Step 2: Preparation of5-bromo-4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(2)

To a solution of 5-bromo-2-chloro-4-methyl-6-(oxetan-3-yloxy)pyrimidine(1) (554 mg, 1.97 mmol) in n-BuOH (16 mL) was addedcis-4-methylcyclohexylamine hydrochloride (412 mg, 2.75 mmol), followedby triethylamine (0.78 mL). The mixture was heated with an oil bath at115° C. for 4 h. After this time, additional cis-4-methylcyclohexylaminehydrochloride (250 mg, 1.67 mmol) and triethylamine (0.40 mL) was added.The reaction was stirred at 115° C. for another 1 h and then cooled andconcentrated in vacuo. The residue was partitioned between water andEtOAc. The organic layer was separated, dried (Na₂SO₄) and concentratedin vacuo. The residue was purified by ISCO chromatography (24 g silicagel, 0-10% EtOAc in hexanes in 40 min) to give the title compound (2)(381 mg, 52%) as a yellow solid. ¹H NMR (CDCl₃, 500 MHz) δ 5.58-5.52 (m,1H), 4.94-4.91 (m, 2H), 54.81-4.78 (m, 2H), 3.87 (bs, 1H), 2.40 (s, 3H),1.76-1.69 (m, 2H), 1.63-1.52 (m, 6H), 1.23-1.15 (m, 1H), 0.92 (d, 3H).

Step 3:4-(4-methyl-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol(3)

To a solution of5-bromo-4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)pyrimidin-2-amine(2) (180 mg, 0.50 mmol) in DMF/dioxane/water (1 mL/1 mL/1 mL) was added4-hydroxyphenylboronic acid (84 mg, 0.60 mmol) followed by Pd(dppf)₂Cl₂(41 mg, 0.05 mmol) and Cs₂CO₃ (489 mg, 1.5 mmol). The mixture was heatedwith an oil bath at 100° C. for 20 minutes. After this time the reactionwas cooled and concentrated in vacuo, then purified by ISCOchromatography (12 g silica gel, 0-25% EtOAc in hexanes in 40 min) togive the title compound (130 mg, 70%) as a yellow solid. ¹H NMR (CH₃OD,300 MHz) δ 7.06-7.01 (m, 2H), 6.83-6.78 (m, 2H), 5.54-5.48 (m, 1H),4.91-4.86 (m, 2H), 4.59-4.54 (m, 2H), 3.96-3.90 (m, 1H), 2.09 (s, 3H),1.82-1.54 (m, 7H), 1.38-1.20 (m, 2H), 0.96 (d, 3H).

Step 4:4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine

To a solution of4-(4-methyl-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol(3) (130 mg, 0.35 mmol) in anhydrous DMF (4 mL) at r.t. was added Cs₂CO₃(344 mg, 1.06 mmol), KI (12 mg, 0.07 mmol) and (R)-tetrahydrofuran-3-yl4-methylbenzenesulfonate (256 mg, 1.06 mmol). The mixture was stirred atr.t. for 4 h, and then was heated at 90° C. for another 0.5 h. Afterthis time the mixture was cooled and extracted with EtOAc. The organiclayer was separated, and dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified using ISCO chromatography (12 g silica gel, 0-25%EtOAc in hexanes in 40 min) to give the title compound (46 mg, 30%) as awhite solid. ¹H NMR (CDCl₃, 500 MHz) δ 7.16-7.14 (m, 2H), 6.90-6.85 (m,2H), 5.95-5.51 (m, 1H), 4.97-4.95 (m, 1H), 4.90-4.84 (m, 2H), 4.62-4.66(m, 2H), 4.05-3.90 (m, 5H), 2.24-2.18 (m, 2H), 2.15 (s, 3H), 1.79-1.75(m, 2H), 1.51-1.65 (m, 6H), 1.27-1.21 (m, 2H), 0.93 (d, 3H). MS (ESI,M+H⁺) C₂₅H₃₄N₃O₄, calcd. 440.2. found 440.2

Example 252 Preparation of methyl2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylateand2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylicacid

Step 1: Preparation of (R)-methyl2-chloro-5-iodo-6-(tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate (1)

To a solution of (R)-(−)-3-hydroxy-tetrahydrofuran (0.214 g, 2.42 mmol)in anhydrous THF (10 mL) at 0° C. was added NaH (60% in mineral oil, 103mg, 2.58 mmol). The mixture was stirred at 0° C. for 30 min, then methyl2,6-dichloro-5-iodopyrimidine-4-carboxylate (0.539 g, 1.62 mmol) wasadded to the mixture at −10° C. The reaction mixture was stirred at thesame temperature for 30 min, and then allow warm to r.t. for 4 h. Thereaction was then diluted with EtOAc and acidified with 2 N HCl. Theaqueous layer was extracted with EtOAc. The organic layer was dried(Na₂SO₄) and concentrated in vacuo. The residue was dissolved in ether(8 mL) and MeOH (2 mL), and then trimethylsilyldiazomethane (2 M, 2 mL,4 mmol) was added at 0° C. The reaction was stirred at r.t. for 1 h, andthen quenched by 2 N HCl and concentrated in vacuo. The residue waspurified by ISCO chromatography (24 g silica gel, 1-10% EtOAc in hexanesin 40 min) to give the title compound (0.140 g, 26%) as a colorless oil.¹H NMR (CDCl₃, 500 MHz) δ 5.69-5.66 (m, 1H), 4.10 (dd, 1H), 4.05-3.92(m, 6H), 2.38-2.30 (m, 1H), 2.24-2.18 (m, 1H).

Step 2: Preparation of methyl5-iodo-2-((1s,4S)-4-methylcyclohexylamino)-6-((R)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate(2)

To a solution of (R)-methyl2-chloro-5-iodo-6-(tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate (1)(140 mg, 0.36 mmol) in n-BuOH (6 mL) was addedcis-4-methylcyclohexylamine hydrochloride (85 mg, 0.55 mmol), followedby triethylamine (0.15 mL, 1.08 mmol). The mixture was heated with anoil bath at 130° C. for 2 h. After this time the mixture was cooled andconcentrated in vacuo. The residue was purified by ISCO chromatography(12 g silica gel, 0-25% EtOAc in hexanes in 40 min) to give the titlecompound (2) (111 mg, 66%) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ5.53-5.47 (m, 1H), 4.11-3.88 (m, 8H), 2.20-2.18 (m, 2H), 1.85-1.71 (m,2H), 1.67-1.47 (m, 5H), 1.23-1.05 (m, 2H), 0.92 (d, 3H).

Step 3: Preparation of methyl2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate

To a solution of methyl5-iodo-2-((1s,4S)-4-methylcyclohexylamino)-6-((R)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate(2) (129 mg, 0.28 mmol) in DMF/dioxane/water (1 mL/1 mL/1 mL) was added4-morpholinophenylboronic acid (70 mg, 0.33 mmol) followed byPd(dppf)₂Cl₂ (23 mg, 0.028 mmol) and Cs₂CO₃ (274 mg, 0.84 mmol). Themixture was heated with an oil bath at 100° C. for 10 min. The reactionthe was cooled and concentrated in vacuo, and then purified by ISCOchromatography (12 g silica gel, 0-50% EtOAc in hexanes in 40 min) togive the title compound (61 mg, 44%) as a white solid. ¹H NMR (CD₃OD,300 MHz) δ 7.12 (d, 2H), 6.94 (d, 2H), 5.60-5.56 (m, 1H), 4.01-3.96 (m,2H), 3.84-3.79 (m, 7H), 3.60 (s, 3H), 3.16 (t, 4H), 2.26-2.06 (m, 1H),2.06-2.00 (m, 1H), 1.85-1.77 (m, 2H), 1.72-1.56 (m, 5H), 1.39-1.28 (m,2H), 0.97 (d, 3H). MS (ESI, M+H⁺) C₂₇H₃₇N₄O₅, calcd. 497.3 found 497.2.

Step 4: Preparation of2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylicacid

To a solution of methyl2-((1s,4R)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)-6-((S)-tetrahydrofuran-3-yloxy)pyrimidine-4-carboxylate(37 mg, 0.074 mmol) in anhydrous THF (3 mL) and water (3 mL) was addedLiOH aqueous solution (1 M, 1.5 mL) at r.t. The mixture was stirred forovernight. After this time the reaction was heated at 50° C. and stirredfor another 16 h. The mixture was diluted with EtOAc and the aqueouslayer was acidified by 2 N HCl. The aqueous layer was extracted withEtOAc. The organic layers were separated, and dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by trituration usingMeOH and dichloromethane to give the title compound (14 mg, 39%) as aoff-white solid. ¹H NMR (CD₃OD, 500 MHz) δ 7.26 (d, 2H), 7.17 (d, 2H),5.71-5.67 (m, 1H), 4.28 (bs, 1H), 3.96 (d, 1H), 3.90 (t, 4H), 3.85 (dd,1H), 3.82-3.73 (m, 2H), 3.36-3.32 (m, 4H), 2.32-2.24 (m, 1H), 2.06-2.01(m, 1H), 1.95-1.86 (m, 2H), 1.81-1.73 (m, 2H), 1.75-1.65 (m, 2H), 1.59(bs, 1H), 1.32-1.22 (m, 2H), 1.00 (d, 3H). MS (ESI, M+H⁺) C₂₆H₃₅N₄O₅,calcd. 483.3. found 483.1.

Example 253 Dual Corrector Potentiator Assay

The ability of exemplary compounds to correct the processing defect ofΔF508 CTFR, i.e. increase the surface expression of CFTR channels, andpotentiate existing channels was demonstrated in an FRT cellelectrophysiological (Ussing chamber) assay. For use in the correctorassay, FRT epithelial cell monolayers are grown on Snapwell filterinserts and optionally treated with a compound of invention, vehicle(DMSO) or reference correctorN-(2-(5-chloro-2-methoxyphenylamino)-4′-methyl-4,5′-bithiazol-2′-yl)pivalamide(C17). Cells are exposed to compound, vehicle (negative control) orreference corrector (positive control) in a cell/tissue incubator at 37°C. for 24 hours prior to the assay. The inserts are then transferred toa Physiologic Instruments Ussing chamber (P2302) and superfused with 5ml of a HEPES buffered physiological saline (HB-PS) as the serosalsolution with composition (in mM): NaCl, 137; KCl, 4.0; CaCl₂, 1.8;MgCl₂, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH. Themucosal solution will be 5 ml of 10CF—PS with composition (in mM):Na-gluconate, 137; KCl, 4; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; Glucose, 10;pH adjusted to 7.4 with N-methyl-D-glucamine to create a transepithelialCl ion gradient. Transepithelial voltage is clamped to 0 mV and theshort circuit current (ISC)—reflecting the net ion (Cl—) transportacross the epithelial cell monolayer—is measured using a PhysiologicInstruments VCC MC8 epithelial voltage clamp (Physiologic Instruments,Inc., San Diego, Calif.). The assay is carried out at 27° C.

After acquisition of at least 10 minutes of baseline current, agonists(final concentrations: 10 μM forskolin, 100 μM3-isobutyl-1-methylxanthine [IBMX] and 20 μM genistein) and antagonist(final concentration: 20 μM CFTRinh-172) will be applied sequentiallyand cumulatively at ˜10-15 minute intervals to both serosal and mucosalepithelial surfaces. On occasion where a 10-15 min interval is notsufficient for ISC to reach a new steady-state after compound addition,the interval between compound additions may have been extended.

Agonists are added as 200×-1000× stock solutions to both the serosal andmucosal sides. Transepithelial resistance is monitored every 20 s. In apotentiator assay, appropriate volumes from 10 mM compound stocksolution in DMSO are added to the mucosal side (i.e. the 10CF—PSsolution containing half chamber) of vehicle treated inserts. Compoundis added acutely after activation of CFTR by Forskolin and prior toadditions of IBMX, genistein, and CFTRinh-172.

Corrector efficacy—as given in Table 3—is measured as the total changein ISC (i.e. the difference in ISC before and after addition of allagonists) obtained from cells treated with 3 μM compound of inventionand normalized to the total change in ISC obtained from the same batchof cells treated contemporaneously with 10 μM reference corrector C17.Potentiator efficacy—as given in Table 3—is measured as the change inISC after acute addition of 1 μM compound to the mucosal side of vehicletreated cells divided by the total change in ISC after sequentialadditions of 1 μM compound, 100 μM IBMX, and 20 μM genistein.

Table 3 provides results for exemplary compounds. Corrector efficacyranges correspond to: +=<0.3, ++=0.3-0.6, and +++=>0.6. Potentiatorefficacy ranges correspond to +=<0.1, ++=0.1-0.25, and +++=>0.25.

TABLE 3 Cor- Poten- Ex- rector tiator ample Effi- Effi- No. CompoundName cacy cacy 1 N,N-dimethyl-3-(2-((1s,4s)-4- +++ ++methylcyclohexylamino)-5-(4-morpholinophenyl)-pyrimidin-4-yloxy)azetidine-1-sulfonamide 64-((R)-tetrahydrofuran-3-yloxy)-5-(4-((S)- ++ ++tetrahydrofuran-3-yloxy)phenyl)-N-(cis-4-methylcyclohexyl)pyrimidin-2-amine hydrochloride salt 434-methyl-N-((1s,4S)-4-methylcyclohexyl)-5-(4- ++ +morpholinophenyl)-6((R)-tetrahydrofuran-3- yloxy)pyrimidin-2-amine 59N-((1s,4s)-4-methylcyclohexyl)-4-(1- ++ +(methylsulfonyl)azetidin-3-yloxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 78N-((1s,4S)-4-methylcyclohexyl)-4-((R)-1- ++ +(methylsulfonyl)pyrrolidin-3-yl)methoxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 80N-((1s,4s)-4-methylcyclohexyl)-4-((1- ++ +++(methylsulfonyl)azetidin-3-yl)methoxy)-5-(4-morpholinophenyl)pyrimidin-2-amine 93N-((1s,4s)-4-methylcyclohexyl)-4-(tetrahydro-2H- +++ ++pyran-4-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine 103 methyl 3-(4-(2-((1s,4S)-4- ++ +methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1- carboxylate 112N,N-dimethyl-3-(4-(2-((1s,4S)-4- ++ +methylcyclohexylamino)-4-((R)-tetrahydrofuran-3-yloxy)pyrimidin-5-yl)phenoxy)pyrrolidine-1- carboxamide 152N-((1s,4s)-4-methylcyclohexyl)-4-(1- +++ +++(methylsulfonyl)piperidin-4-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2- amine 1535-(4-(2-methoxyethoxy)phenyl)-N-((1s,4s)-4- ++ +methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine 170 N-(2,6-dimethylcyclohexyl)-4-((R)- +++ +tetrahydrofuran-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2- amine 206 methyl4-(5-(4-(2-methoxyethyl)phenyl)-2- ++ +((1s,4s)-4-methylcyclohexylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate 207 N,N-dimethyl-3-(2-((1s,4s)-4- +++ +methylcyclohexylamino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide 214 N,N-dimethyl-3-(2-((1s,4s)-4- +++ +methylcyclohexylamino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide 2154-(1-(cyclopropylsulfonyl)azetidin-3-yloxy)-N- +++ +++((1s,4s)-4-methylcyclohexyl)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2- amine

REFERENCES

All publications and patents mentioned herein, including those itemslisted below, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually incorporated by reference. In case of conflict, the presentapplication, including any definitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt or N-oxide thereof, wherein: R₁ is—O—(CR₆R₇)_(n)-A₂, —N(R₆)(CR₆R₇)_(n)-A₂, —S—(CR₆R₇)_(n)-A₂, orheterocycloalkyl, wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀; R₂ is—O-heterocycloalkyl, —O-heterocycloalkenyl, —Y-heterocycloalkyl,—Y-heterocycloalkenyl, heterocycloalkyl, -heterocycloalkenyl,-cycloalkyl, -cycloalkenyl, —(CR₆R₇)_(n)—C₁-C₆alkoxyl,—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl, C₁-C₆alkoxyl, halogen, —CF₃, —CH₂F, —CHF₂,—OCF₃, —OCH₂F, hydroxyl, or C₁-C₆alkyl, wherein said heterocycloalkyl,heterocycloalkenyl, cycloalkyl, and cycloalkenyl are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂,—OCF₃, —N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉,—N(R₈)COR₁₀, —N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀;R₃ is hydrogen, halogen, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₆alkoxyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —OCF₃, —OCH₂F,—N(R₈)R₉, —CN, —C(O)R₁₀, —CO₂R₈, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, or —SO₂R₁₀; R₄ is hydrogen, halogen, C₁-C₄alkyl,cyclopropyl, —CN, or —CF₃; R₅ is hydrogen or C₁-C₄alkyl; R₆ and R₇ eachrepresent independently for each occurrence hydrogen or alkyl, or whenR₆ and R₇ are attached to the same atom, R₆ and R₇ are optionally takentogether with the atom to which they are attached to form a 3-6 memberedcycloalkyl or heterocycloalkyl group; R₈ and R₉ each representindependently for each occurrence hydrogen, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; or whenR₈ and R₉ are attached to the same atom, R₈ and R₉ are optionally takentogether with the atom to which they are attached to form a 3-6 memberedcycloalkyl or heterocycloalkyl group; R₁₀ represents independently foreach occurrence alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,aralkyl, or heteroaralkyl; A₁ is phenylene or a monocyclic heteroarylenegroup; A₂ is a heterocycloalkyl group containing at least one nitrogenor sulfur atom, and wherein said heterocycloalkyl group is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₆alkoxyl, C₃-C₆cycloalkyl, hydroxyl, —CF₃, —CH₂F, —CHF₂, —N(R₈)R₉,—CN, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀, —N(R₈)SO₂R₁₀,—SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀; W is C₁-C₆alkyl orC₄-C₁₀cycloalkyl, each of which are optionally substituted with one,two, or three substituents independently selected from the groupconsisting of C₁-C₆alkyl, C₁-C₆haloalkyl, cycloalkyl, —OC₁-C₆alkyl,—O-cycloalkyl, —OH, —CF₃, and fluoro; Y is —N(R₈)—, —S—, —S(O)—, or—S(O)₂—; m is 1 or 2; and n is 0, 1, 2, 3, or
 4. 2. The compound ofclaim 1, wherein R₁ is —O—(CR₆R₇)_(n)-A₂ or a heterocycloalkyl groupoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀.
 3. Thecompound of claim 1, wherein R₁ is —O—(CR₆R₇)_(n)-A₂.
 4. The compound ofclaim 3, wherein A₂ is a heterocycloalkyl group containing at least onenitrogen or sulfur atom, and wherein said heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl,C₃-C₆cycloalkyl, —C(O)R₁₀, —CO₂R₈, —OC(O)R₉, —CON(R₈)R₉, —N(R₈)COR₁₀,—N(R₈)SO₂R₁₀, —SO₂N(R₈)R₉, —N(R₈)SO₂N(R₈)R₉, and —SO₂R₁₀.
 5. Thecompound of claim 3, wherein A₂ is a heterocycloalkyl group containingat least one nitrogen or sulfur atom, and wherein said heterocycloalkylgroup is substituted with one or more substituents independentlyselected from the group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉,and —SO₂R₁₀.
 6. The compound of claim 3, wherein A₂ is azetidinyl,pyrrolidinyl, or piperidinyl, each substituted with —CON(R₈)R₉, —CO₂R₈,—SO₂N(R₈)R₉, or —SO₂R₁₀.
 7. The compound of claim 3, wherein A₂ is oneof the following:


8. The compound of claim 1, wherein R₂ is —O-heterocycloalkyl or—O—(CR₆R₇)_(n)—C₁-C₆alkoxyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆alkyl, —CO₂R₈, —CON(R₈)R₉,—SO₂N(R₈)R₉, and —SO₂R₁₀.
 9. The compound of claim 1, wherein R₂ is—O-heterocycloalkyl; wherein said heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of —CO₂R₈, —CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀.10. The compound of claim 1, wherein R₂ is morpholinyl,—O-tetrahydrofuranyl, O-tetrahydropyranyl, —O-pyrrolidinyl, O-azetidinylor —O-piperidinyl; wherein said pyrrolidinyl, azetidinyl or piperidinyleach independently is optionally substituted with one or moresubstituents independently selected from the group consisting of —CO₂R₈,—CON(R₈)R₉, —SO₂N(R₈)R₉, and —SO₂R₁₀.
 11. The compound of claim 1,wherein R₂ is —O-tetrahydrofuranyl.
 12. The compound of claim 1, whereinR₃ is hydrogen, halogen, —OCF₃, —OCH₂F, —CF₃, C₁-C₆alkyl, orC₁-C₆alkoxyl.
 13. The compound of claim 1, wherein R₈ and R₉ eachrepresent independently for each occurrence hydrogen, methyl, ethyl orcyclopropyl.
 14. The compound of claim 1, wherein R₁₀ is methyl, ethyl,n-propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, phenyl, or benzyl.15. The compound of claim 1, wherein A₁ is phenylene.
 16. The compoundof claim 1, wherein W is C₅-C₁₀cycloalkyl optionally substituted withone or two substituents independently selected from the group consistingof C₁-C₆alkyl, —CF₃, and fluoro.
 17. The compound of claim 1, wherein Wis cyclohexyl substituted with one or two substituents independentlyselected from the group consisting of C₁-C₆alkyl, —CF₃, and fluoro. 18.The compound of claim 1, wherein the compound is selected from the groupconsisting of:N,N-dimethyl-3-(2-((1s,4S)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;methyl4-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-morpholinophenyl)pyrimidin-4-yloxy)piperidine-1-carboxylate;N-((1s,4s)-4-methylcyclohexyl)-4-(1-(methylsulfonyl)piperidin-4-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-((R)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;N,N-dimethyl-3-(2-((1s,4s)-4-methylcyclohexylamino)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-4-yloxy)azetidine-1-sulfonamide;and4-(1-(cyclopropylsulfonyl)azetidin-3-yloxy)-N-((1s,4s)-4-methylcyclohexyl)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine;or a pharmaceutically acceptable salt or N-oxide thereof.
 19. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 20. A method of treating cysticfibrosis, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of claim 1.